Dear readers of ADxS.org, please forgive the disruption.

ADxS.org needs about $53200 in 2024. In 2023 we received donations from third parties of about $ 32200. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2024 would be over after a few days. This donation request is displayed 19,000 times a week, but only 40 people donate. If you find ADxS.org useful, please take a minute and support ADxS.org with your donation. Thank you!

Since 01.06.2021 ADxS.org is supported by the non-profit ADxS e.V..

$3391 of $53200 - as of 2024-02-01
6%
Header Image
CES1 Metabolizing enzyme

Sitemap

CES1 Metabolizing enzyme

8.3.3. CES1

Carboxylesterase 1 (CES1) is the most abundant enzyme in the liver (about 1 % of liver proteins). CES1 causes 80 to 95 % of hydrolysis in the liver. It is also found to a lesser extent in the lungs and brain.
In addition to its important role in the degradation of xenobiotic compounds, CES1 appears to be involved in endogenous metabolic functions, e.g. in relation to:1

  • Cholesterol esters
  • Triglycerides
  • bioactive lipids

Methylphenidate is primarily degraded to ritalinic acid (aphenyl-2-piperidine acetic acid) by carboxylesterase 1A1 (CES1) in the liver.2 The earlier assumption that MPH is metabolized by hepatic lysozyme enzymes is outdated.3
CES1 predominantly degrades L-MPH, less degrades d-MPH. Therefore, more d-MPH (dexmethylphenidate) remains in plasma. Most MPH preparations contain a racemic mixture of d- and L-MPH, with only d-MPH being pharmacologically active.4 60 to 80% of the ingested MPH is excreted in the urine as ritalinic acid.5

  • aromatic hydroxylation to p-hydroxy-methylphenidate (p-hydroxy-MPH)4 share between 1.5 and 12 % of the degradation.
  • microsomal oxidation 6-oxo-methylphenidate (6-oxo-MPH; inactive metabolite)4 fraction to 2.5% of MPH.
  • unchanged excretion of MPH is reported to be less than 1%5 to with urine: 2%, in feces: 3%4

CYP enzymes are not involved in the degradation of MPH.678 One study found no association between different metabolizing gene variants of CYP2D6 or CYP2C19 (only an increased rate of CYP2C19 ultra-metabolizers among ADHD sufferers).9
Therefore, there is only a relatively low risk of drug interactions.3

The activity of CES1 is highly variable. What contributes to this variability was still largely unknown in 2018.10
There are large individual differences in the response to many drugs metabolized by CES1.1 The expression and activity of CES1 varies widely in humans. Therefore, significant individual differences in CES1-based pharmacokinetics and pharmacodynamics may exist. The bioavailability of MPH varies from 11% to 53% in children.11 Factors affecting degradation by CES1 are non-genetic or genetic in nature:12

8.3.3.1. Non-genetic factors affecting CES1 metabolism
  • Development status
  • Gender
  • Drug-drug interactions (see substrates, inhibitors, inducers)

The level of CES1 expression is related to the level of methylation of the CpG islands (CGIs) of the CES1 promoter. Melatonin decreases the level of methylation of the CES1 promoter by promoting the expression of sirtuin 1 (SIRT1), which mediates the deacetylation of DNA methyltransferase 1 (DNMT1).13

8.3.3.2. Genetic influences affecting CES1 metabolism
8.3.3.2.1. CES1 haplotypes, hybrid genes

Two haplotypes of CES1 are known:1410

  • the first haplotype (“wild type”) is a hybrid gene from
    • CES1P1
      • CES1P1 (CES1A3) is an inactive truncated pseudogene. It is located near CES1 on chromosome 16. CES1P1 appears to have arisen by gene replacement.
    • CES1A1 (prototype of CES1)
  • the second haplotype is a hybrid gene from
    • CES1A1
    • CES1A2 (a CES1-like variant)
      • A computational modeling study found significantly reduced MPH degradation and approximately 70% higher d-MPH plasma exposure in two CES1A2 copies compared with the wild-type genotype14
      • A CES1A2 copy caused approximately 22% higher MPH levels14
      • CES1A2 showed increased degradation in relation to irinotecan15
      • A clinical trial with oseltamivir found no effect of CES1 diplotype on degradation16
      • A study of 99 children on MPH found:17
        • the overall average MPH dose was 0.79 mg/kg/day.
        • the mean MPH dose by haplotype was
          • CES1A2/CES1A2: 0.92 mg/kg for
          • CES1A2/CES1P1: 0.81 mg/kg
          • CES1P1/CES1P1: 0.78 mg/kg

Therefore, some individuals carry two almost identical CES1 copies on the same chromosome.1
In four CES1 copies, MPH degradation was lowest, and MPH AUC was approximately 1.5 times higher than in the control group18
With two or three copies of CES1, MPH degradation was only slightly reduced18

Hybrid gene variants are:

  • CES1P1 with CES1
    • higher transcriptional activity than CES1P1
  • CES1A2 (another hybrid gene variant of CES1 and CES1P1)
    • has 2% of the transcriptional efficiency of CES1
  • CES1A1b
  • CES1A1c (CES1VAR)
    • has no noticeable effect on the metabolism of drugs10

CES1 gene variants with functional effects are rare. The major factors affecting CES1 metabolism appear to depend on other influences10

To date, nearly 200 variants have been found in the CES1 / CES1P1 gene region.1

  • genetic polymorphisms
    • Single nucleotide polymorphisms (SNPs)
      • Over 2500 single nucleotide polymorphisms (SNPs) have been identified in the CES1 gene (NCBI dbSNP). Some SNPs, such as G143E, D269fs, E220G, and L40T, are deleterious to the enzymatic activity of the gene and could alter CES1-mediated drug metabolism. However, these variants account for only a small portion of CES1 variability, leaving the majority unexplained.19
      • G143E (rs71647871)
        • Frequency; 3.7% in Caucasians20
        • G143E carriers required less MPH,10 21 in one study it was 28% less22 with up to 2.5-fold d-MPH AUC observed at the same dose of MPH.18 and one-third of MPH metabolization23
        • Subjects who were heterozygous for the CES1 variant G143E (p.Gly143Glu of rs71647871)
          • metabolized MPH significantly slower14, about half as fast as non-carriers24
            • male G143E carriers who consume alcohol are likely to be at higher risk for MPH overexposure
          • p.Gly143Glu (rs71647871) appears to significantly impair the metabolism of:1
            • Methylphenidate
            • Trandolapril
            • Oseltamivir
        • A computational modeling study found rs71647871 to be a very important covariate in determining interindividual differences in MPH metabolism. rs71647871 GA resulted in a 2.4-fold increase in plasma d-MPH exposure. rs71647871 may be a risk factor for adverse MPH effects14
      • rs115629050 TG (p.Ala270Ser)
        • An in silico simulation showed significantly reduced MPH degradation with approximately 68% higher d-MPH plasma exposure compared with the wild-type genotype. For rs115629050 TG, scores were equal to or greater than those of rs71647871 GA in 6 of 9 models14
        • rs115629050 decreases CES125
        • In vitro, rs115629050 TG showed no effect on drug metabolism with respect to angiotensin26
      • E220G (c.662A>G, rs200707504) is reported to be associated with decreased CES1 activity27
      • c.428G>A (p.Gly143Glu, rs121912777) is reported to be associated with decreased CES1 activity27
      • c.780delT (p.Asp260fs, rs71647872) is reported to be associated with decreased CES1 activity27
      • c56G>T (rs3826190) is reported to be associated with decreased CES1 activity27
      • c.808G>T (rs115629050) is reported to be associated with decreased CES1 activity27
      • rs114119971 may be associated with decreased CES1 activity:17
        • mPH dose in the 2 (of 99) affected children was an overall average of 0.42 mg/kg/day compared with subjects without SNV of 0.88 mg/kg/day
      • S75N (rs2307240)
        • appears to increase the activity of CES1 in relation to clopidogrel28
        • does not appear to affect CES1 activity in relation to methylphenidate in children29
      • rs3815589
        • does not appear to affect CES1 activity in relation to methylphenidate in children30
      • rs2287194
        • does not appear to affect CES1 activity in relation to methylphenidate in children31
      • rs2244613
        • does not appear to affect CES1 activity in relation to methylphenidate in children32
        • correlated significantly with sadness as a side effect of unretarded MPH in A/A subjects
        • rs2244613-G showed an increased side effect risk of MPH in comorbid ASA33
      • rs2002577
        • does not appear to affect CES1 activity in relation to methylphenidate in children34
        • tended to correlate with sadness as a side effect of unretarded MPH in G/G subjects
      • rs2307244
        • does not appear to affect CES1 activity in relation to methylphenidate in children35
      • rs12443580
        • does not appear to affect CES1 activity in relation to methylphenidate in children36
      • the 75 T/G and 75 G/G polymorphisms appear to be associated with greater appetite loss with MPH use compared with the T/T variant.37
      • different CES1A2 promoter haplotypes are reported to be associated with increased CES1 expression:1
        • 47C,
        • 46T
        • 41G
        • 40
        • 37C
        • 34G
        • 32T
  • rs2307235-A
    • increased side effect risk of MPH with comorbid ASA33
  • rs8192950-T
    • increased side effect risk of MPH with comorbid ASA33
  • rs2302722-C
    • reduced side effect risk of MPH in comorbid ASA33
    • Copy number variants4
      • The different CES1 variants exist in multiple haplotypes and diplotypes. Individuals can carry more than two active copies of CES1 (i.e., two CES1 copies and one CES1A2 copy for a copy number of three or two CES1 copies and two CES1A2 copies for a copy number of four).
        • Individuals may carry more than two active copies of CES1
      • One study found reduced degradation, contrary to the expectation that higher copy number should be associated with increased degradation:
        • Carriers of 4 copies of CES1 had 45% (P = 0.011) and 61% (P = 0.028) higher d-MPH levels (AUC) than control subjects or carriers of 3 copies of CES1, respectively.

Stevens et al compiled studies that addressed influences of gene variants on the effects of MPH:4

8.3.3.2.2. Neurotransmitter synthesis and degradation
  • TH gene38
    • Rs2070762 C/C: Decreased response (CGI-I)
  • DBH gene38
    • Rs1541332 TC Haplotype: Increased Treatment Failure (CGI-S)
    • Rs2073833 TC Haplotype: Increased Treatment Failure (CGI-S)
    • Rs2073833 C/C: Increased treatment failure (CGI-I)
  • DBH gene38
    • Rs2007153 AGC haplotype: reduced risk of adverse events
    • Rs2797853 AGC haplotype: reduced risk of adverse events
    • Rs77905 AGC haplotype: reduced risk of adverse events
  • TPH2 gene39
    • Rs1386488 CGCAAGAC (‘Yang’ haplotype): greater score improvement by MPH (TOVA) than AATGGAGA (‘Yin’ haplotype)
    • Rs2220330 CGCAAGAC (‘Yang’ haplotype): greater score improvement by MPH (TOVA) than AATGGAGA (‘Yin’ haplotype)
    • Rs1386495 CGCAAGAC (‘Yang’ haplotype): greater score improvement by MPH (TOVA) than AATGGAGA (‘Yin’ haplotype)
    • Rs1386494 CGCAAGAC (‘Yang’ haplotype): greater score improvement by MPH (TOVA) than AATGGAGA (‘Yin’ haplotype)
    • Rs6582072 CGCAAGAC (‘Yang’ haplotype): greater score improvement by MPH (TOVA) than AATGGAGA (‘Yin’ haplotype)
    • Rs1386492 CGCAAGAC (‘Yang’ haplotype): greater score improvement by MPH (TOVA) than AATGGAGA (‘Yin’ haplotype)
    • Rs4760814 CGCAAGAC (‘Yang’ haplotype): greater score improvement by MPH (TOVA) than AATGGAGA (‘Yin’ haplotype)
    • Rs1386497 CGCAAGAC (‘Yang’ haplotype): greater score improvement by MPH (TOVA) than AATGGAGA (‘Yin’ haplotype)
  • MAOA
    • 30-bp promoter VNTR 4-repeat allele vs 3-repeat allele Improved response (SNAP-IV oppositional)40
    • 30-bp promoter VNTR 4- and 5-repeat alleles Improved values for impulsivity (TOVA)41
  • COMT
    • Rs4680 c/G
      • Increased response rate (ADHD-RS, CGI-S)42, (K-ARS)43, (metastudy)44
      • Increased irritability45
    • Rs4680 G: Increased sadness46

There is evidence that decreased expression of the CACNA1C gene may lead to a prolonged effect of dopamine reuptake inhibitors.47 Conversely, increased expression is likely to result in a shortened effect.

8.3.3.2.3. Neurotransmitter reuptake transporter genes
  • SLC6A2 - noradrenaline transporter gene

    • Rs28386840 A/A Reduced response (CGI-I)48
    • Rs28386840 A/A Reduced response (TOVA)49
    • Rs28386840 A/A Reduced response (ADHD-RS and CGI-I)50
    • Rs28386840 T Enhanced response (metastudy)44
    • Rs28386840 T/T Increased HR51
    • Rs5569 G Increased response (ADHD-RS)52
    • Rs5569 G/G Increased response (ADHD-RS and CGI-S)53
    • Rs5569 G/G Increased response (TOVA)49
    • Rs5569 N/A Increased response (metastudy)44
  • SLC6A3 - Dopamine transporter gene

    • Rs28363170 absence of 10R alleles:
      • Improved hyperactive-impulsive scores (Vanderbilt ADHD Parent and Teacher Rating Scales)54
      • DAT 9/9: stronger response to MPH than 9/10 and 10/1055
      • 9R/9R: Reduced Response (ADHD-RS)56
      • 10R/10R: Improvements in working memory (N-Back Test)57
      • 10R/10R: Reduced response (meta-analysis, naturalistic studies)58
      • 10R/10R: Reduced response (metastudy)44
    • Rs2550948 G: Amplified response (CGI-S)59
  • SLC6A4 - Serotonin transporter gene

    • 5HTTLPR L/L (i.e., DRD4 7R carriers) Minor symptom improvement (CGAS)60
    • 5HTTLPR L Lower math values (PERMP)45
    • 5HTTLPR L/L Decreasing vegetative symptoms (sleep problems and loss of appetite)45
    • 5HTTLPR L Increased nail biting61
    • 5HTTLPR L Increased tics61
    • 17-bp VNTR Lack of 12R allele Minor symptom improvement (ADHD-RS)45
    • 17-bp VNTR 12R/12R Decreased response rate (CGI-I and ABC subscale for hyperactivity)62
8.3.3.2.4. Receptor genes
  • DRD1
    • Rs4867798 G Enhanced response (CGI-I and ABC hyperactivity subscale)62
    • Rs5326 A Increased response (CGI-I and ABC hyperactivity subscale)62
  • DRD2
    • Rs2283265 T (MPH dose as covariate) Increased risk of an adverse event38
    • A2/A2 stronger response to MPH than A1/A1 and A1/A255
  • DRD3
    • Rs6280 A/A Increased response (CGI-I and ABC hyperactivity subscales)62
    • Rs2134655 Carriers of G for both SNPs Increased treatment failure (CGI-I)38
    • Rs1800828 Carriers of G for both SNPs Increased treatment failure (CGI-I)38
  • DRD4
    • 48-bp VNTR
      • 4R/4R:
        • Enhanced response (ADHD-RS)63
        • Enhanced response (metastudy)44
      • Absence of 4R alleles: lower improvement in hyperactive-impulsive scores (Vanderbilt ADHD Parent and Teacher Rating Scales)54
      • 7R:
        • Increased response and gene transfer (TDT)64
        • (combined with L/L genotype of SLC6A4 5HTTLPR): Reduced response (CGAS)60
        • Increased dose required for response (Conners’ Global Index-Parent)65
    • 120-bp promoter duplication
      • L/L: Amplified response (Teacher CLAM-SKAMP)66
      • S/S: Reduced response (CGAS and CGI-S)59
    • Rs11246226 A/A: Increased response (CGI-S and ABC subscale for hyperactivity)62
  • ADRA2A - Adrenoceptor Alpha 2 A Gene
    • Rs1800544 G
      • Reduced inattention (SNAP-IV)6768
      • Increased response (metastudy)44
    • Rs1800544 G/G Increased Response (ADHD-RS Parent)69
    • Rs1800544 C/C Increased diastolic blood pressure51
8.3.3.2.5. Neurotransmitter release
  • SNAP25
    • Rs3746544 T/T
      • Improved Response (ADHD-RS)70
      • Reduced response (CGI-S)59
    • Rs3746544 G: Reduced irritability66
    • Rs1051312 C66
      • Decreased motor tics
      • Decreased buccal-lingual movements
      • Reduced picking/biting
8.3.3.2.6. Neuronal plasticity and synaptic effectors
  • ADGRL3 - Latrophilin 3 (LPHN3) gene
    • Rs6858066 AAG Haplotype: Reduced Response (CGI-I)71
    • Rs1947274 AAG haplotype: reduced response (CGI-I)71
    • Rs6858066 AAG Haplotype: Reduced Response (CGI-I)71
    • Rs6551665 GCA haplotype: enhanced response (CGI-I)71
    • Rs1947274 GCA haplotype: enhanced response (CGI-I)71
    • Rs6858066 GCA haplotype: enhanced response (CGI-I)71
    • Rs6551665 G: Reduced Response (RAST)72
    • Rs1947274 C: Attenuated response (RAST)72
    • Rs6858066 G:
      • Increased response (RAST)72
      • Attenuated response (RAST)72
    • Rs6813183 CGC Haplotype:
      • Increased response (SNAP-IV)7373
    • Rs1355368 CGC haplotype: increased response (SNAP-IV)73
    • Rs1868790 A/A Reduced response (CGI-S)59
  • BDNF - Brain derived neurotrophic factor - gene (growth factor)
    • Rs6265 G/G Increased response (CGI-S)74
  • NTF3 - Neurotrophin-3 gene
    • Rs6332 A/A
      • Increased emotionality75
      • Increased over-focusing/euphoria75
      • Increased tendency to cry75
      • Increased nail biting75
  • GRM7 - Metabotropic glutamate receptor 7 gene
    • Rs3792452 G/A Enhanced response (ADHD-RS parent, CGI-I)76
  • GRIN2B - Glutamate [NMDA] receptor subtype epsilon-2 (also N-methyl-D-aspartate receptor subtype 2B) gene
    • Rs2284411 C/C Improved Response (ADHD-RS inattentive, CGI-I)77
8.3.3.2.7. Downstream neurotransmitter effects
  • ACT1
    • Intron 3 VNTR: H/H > H/L > L/L: Increased DA release78
8.3.3.2.8. CYP2D6 -gene variants influence effect of MPH and ATX

Although MPH is degraded by CES1 and not by CYP2D6, different CP gene variants showed significant influence on MPH efficacy:79

A3 improvement in ADHD symptomatology on MPH administration was found in CYP2D6 gene variants

  • rs1065852 ‘GG’
  • rs1135840 ’CG
  • rs28363170 10R

In contrast, an improvement in symptoms after atomoxetine was found in the CYP2D6 gene variants

  • rs1135840 ’CC
  • rs28363170 9R
8.3.3.3. CES1: Substrates/Inhibitors/Inductors

*This list - like all information from ADxS.org - is not intended for your own therapeutic use. Even though we try to collect all information, the list is nevertheless incomplete. Errors can also not be excluded. Please ask your doctor or pharmacist. *

The smaller IC50 is, the higher is the therapeutic potency of an active ingredient.
The smaller Ki is, the greater the binding affinity and the smaller the amount of drug required to inhibit the activity of the enzyme.
If Ki is much greater than the maximum drug concentration to which a patient is exposed during typical administration, the drug is unlikely to inhibit the activity of the enzyme.80
The inhibition constant Ki is the inhibitor concentration at which half of the enzymes are inhibited.
Ki reflects the binding affinity, IC50 rather designates the functional strength of the inhibitor for a drug. Ki takes IC50 into account in its calculation.
Non-competitive enzyme inhibition: Ki approximately equal to IC50
Competitive / uncompetitive inhibition: Ki is approx. 1/2 of IC50

8.3.3.3.1 CES1 substrates

CES1 is critical for the degradation of various drugs.12

  • 11-Deoxyalisole A (triterpenoid)
  • 2-oxo-clopidogrel (anticoagulant)81
  • 25-O-ethylalisole A (triterpenoid)
  • Alismanol B (triterpenoid)
  • Alismanol D (triterpenoid)
  • Alismanol F (triterpenoid)
  • Amphetamines (CNS agent)25
    • METH
    • Although predominantly through CYP2D6
  • Benzapril (ACE inhibitor,angiotensin receptor neprilysin inhibitor, ARNI)81
  • Capecitabine (cancer drug)
  • Cholesterol (Endogenous compound
  • Ciclesonide (immunosuppressive agent, adrenal glucocorticoid)81
  • Cilazapril (angiotensin receptor neprilysin inhibitor, ARNI)81
  • Clopidogrel (anticoagulant)82
  • Dabigatran exilate (anticoagulant)82
  • Delapril (angiotensin receptor neprilysin inhibitor, ARNI)81* Clofibrate (antihyperlipidemic)81
  • Dimethyl fumarate (MS agent)
  • Enalapril (ACE inhibitor, angiotensin receptor neprilysin inhibitor, ARNI)81
  • Fenofibrate (antihyperlipidemic agent)81
  • Fatty acid ethyl ester (endogenous compound)
  • Fosinopril (angiotensin receptor neprilysin inhibitor, ARNI)81
  • Flumazenil (CNS agent)
  • Heroin (CNS active ingredient)
  • Imidapril (ACE inhibitor, angiotensin receptor neprilysin inhibitor, ARNI)8281
  • Irinotecan (cancer drug)
  • Cocaine(CNS agent)
  • Lovastatin (antihyperlipidemic agent)81
  • Meperidine (CNS agent)
  • Methylphenidate (CNS agent)
  • Moxeipril (angiotensin receptor neprilysin inhibitor, ARNI)81
  • Mycophenolate mofetil (immunosuppressive agent)
  • Nintedanib (cancer drug)81
  • Oseltamivir (antiviral agent)82
  • Oxybutynin (anticholinergic; used, among other things, for urinary incontinence; antispasmodic)81
  • Para-nitrophenyl valerate (pesticide)
  • Perindopril81
  • Quinapril (ACE inhibitor, angiotensin receptor neprilysin inhibitor, ARNI)81
  • Ramipril (ACE inhibitor, angiotensin receptor neprilysin inhibitor, ARNI)81
  • Rufinamide (CNS agent)
  • Sacubitril (angiotensin receptor neprilysin inhibitor, ARNI; antihypertensive agent)81
  • Sarin (chemical warfare agent)
  • Simvastatin (antihyperlipidemic)81
  • Sofosbuvir (antiviral agent)
  • Soman (Chemical warfare agent)
  • Tabun (Chemical Warfare Agent)
  • Telotristat ethyl (tryptophan hydroxylase inhibitor)81
  • Telotristat etiprat (cancer drug)
  • Temocapril (angiotensin receptor neprilysin inhibitor, ARNI)81
  • Tenofoviralafenamide (antiviral agent)
  • Trandolapril (ACE inhibitor, angiotensin receptor neprilysin inhibitor, ARNI)81
  • Trans-permethrin (pesticide)
  • Travoprost (prostaglandin analog)81
8.3.3.3.2 CES1A1 inhibitors

These agents should therefore not be combined with MPH if possible. We hypothesize that for superfast metabolizers, however, such a combination could be helpful, with at the same time particularly close medical control.

  • 11-Deoxo-glycyrrhetinic acid (IC50: 10.5 µM) (triterpenoid)
  • 1,12-Epoxy-5E,8E,14E- Eicosatrienoic acid (IC50: 27 µM) (Vegetable fatty acid)
  • 15-Deoxy-12,14-prostaglandin J2 (IC50: 12 µM) (Vegetable fatty acid)
  • 22(R)-hydroxycholesterol (unsaturated fatty acid, weak)8383
  • 24(S)-hydroxycholesterol (unsaturated fatty acid, weak)83
  • 24(S),25-Epoxycholesterol (IC50=8.1 μM) (unsaturated fatty acid, moderate)83
  • 25-hydroxycholesterol (unsaturated fatty acid, weak)83
  • 27-Hydroxycholesterol (27-HC) (IC50=33 nM, Kiapp=10 nM) (unsaturated fatty acid, partial noncompetitive inhibitor)83
    • impaired intracellular CES1 activity after treatment of intact THP1 cells
  • 3-O-(-carboxypropionyl)-11-deoxo-glycyrrhetinic acid 30-ethyl ester (IC50: 20.4 µM) (triterpenoid)
  • 4,15-Epoxy-5E,8E,11E-Eicosatrienoic acid (IC50: 38 µM) (Vegetable fatty acid)
  • 7-ketocholesterol (unsaturated fatty acid, weak)83
  • Alcohol (strong) 8411
    • In case of simultaneous intake of alcohol and MPH:84
      • increases the MPH concentration in humans
      • alcohol inhibits CES1-mediated MPH degradation by catalyzing MPH to ethylphenidate1185
        • more l-ethylphenidate (pharmacologically ineffective) seems to be produced than d-ethylphenidate86
        • Ethylphenidate appears to be toxic
        • Ethylphenidate correlates with significantly higher plasma d-MPH levels and enhanced euphoric effects11
        • Ethylphenidate binds similarly strongly to DAT but less strongly to NET than MPH86
  • Arachidonic acid (strong) (IC50: 2 µM; Ki: 1.7 µM) (Vegetable fatty acid)83
    • strongest fatty acid inhibitor of recombinant CES1
    • acted by a non-competitive mechanism (Kiapp=1.7 μM)
  • Aripiprazole (strong) (IC50: 5.7 µM)8711
  • Asian acid (triterpenoid), (Ki: 0.64 µM) (strong)81
  • Bavachinin (strong) (Ki: 0.5 µM) (vegetable, phenol)81
  • Bakuchiol (vegetable)81
  • Benzoic acid-4-O–D-(6-galloyl)-glucopyranoside (vegetable, phenol)81
  • Brevifolin (herbal)81
  • Cannabidiol (cannabinoid), (Ki: 0.974 µM) (strong)81
  • Cannabinol (cannabinoid), (Ki: 0.263 µM) (strong)81
  • Celastrol (triterpenoid), (Ki: 4.43 µM) (strong)81
  • Cholesterol (unsaturated fatty acid, weak)83
  • Corilagina (vegetable)81
  • Coryfolin (strong) (Ki: 1.9 µM) (vegetable, phenol)81
  • Corylin (strong) (Ki: 0.7 µM) (vegetable, phenol)81
  • Corylifol A (vegetable, phenol)81
  • Coryfolinin (Ki: 9.4 µM) (vegetable, phenol)81
  • Desmethoxyyangonin (Ki = 25.2 μM)88
  • Dihydrocavain (Ki = 105.3 μM)88
  • Dihydromethysticin (Ki = 68.2 μM)88
  • Dihydrotanshinone (strong) (Ki: 0.39 µM) (tanshinone)
  • Ellagic acid-4-O-D-glucopyranoside (vegetable, phenol)81
  • Euphorbic acid (triterpenoid)
  • Euphorbine A (triterpenoid)
  • Euphorbine B (triterpenoid)
  • Euphorbine C (triterpenoid)
  • Fatty acids inhibit CES183
    • especially unsaturated fatty acids
  • Fluoxetine (strong) (IC50: 6.1 µM)8711
  • Gallic acid-4-O–D-(6-O-galloyl)-glucopyranoside (vegetable, phenol)81
  • Gallic acid-3-O-D-(6-O-galloyl)-glucopyranoside (vegetable, phenol, phenol)81
  • Gambogic acid81
  • Glycyrrhetinic acid (triterpenoid), (Ki: 13 µM) (strong)81
  • Isobavachalcone (vegetable, phenol)81
  • Kaempferol (flavonoid), (Ki: 62 µM)81
  • Cavain (Ki = 81.6 μM)88
  • Kryptotanshinone (tanshinone), (Ki: 0.54 µM) (strong)81
  • Kuwanon G (vegetable, phenol)81
  • Linoleic acid (strong)(IC50: 9 µM) (Vegetable fatty acid)
  • Linolenic acid (IC50: 19 µM) (Vegetable fatty acid)
  • Luteolin (flavonoid), (Ki: 5.34 µM) (strong)81
  • Methysticin (Ki = 35.2 μM) (Kavalactone)88
  • Miltiron (strong) (Ki: 0.39 µM) (Tanshinon)
  • Myristic acid (strong) (IC50: 9 µM) (Vegetable fatty acid)
  • Myristoleic acid (IC50: 12 µM) (Vegetable fatty acid)
  • Naringenin (flavonoid), (Ki: 30 µM)81
  • Neobavaisoflavones (strong) (Ki: 5.3 µM) (vegetable, phenol)81
  • Oleic acid (strong) (IC50: 7 µM) (Vegetable fatty acid)
  • Oheno (vegetable, phenol)81
  • Oleanolic acid (triterpenoid), (Ki: 0.28 µM) (strong)81
  • Oxysterol83
    • Cholesterol metabolite; also inhibits CES1
  • Pachymic acid (triterpenoid), (Ki: 21.7 µM)81
  • Paeoveitol B (vegetable, phenol)81
  • Palmitic acid (IC50: 25 µM) (Vegetable fatty acid)
  • Palmitoleic acid (strong) (IC50: 7 µM) (Vegetable fatty acid)
  • Perphenazine (strong) (IC50: 13.9 µM)8711
  • Pyron-2-O–D-(6-Galloyl)-Glucopyranoside (vegetable, phenol)81
  • Pyron-2-O–D-(2,6-digalloyl)-glucopyranoside (vegetable, phenol)81
  • Pryomeconic acid-3-O–D-glucopyranoside-6-(O-4-hydroxybenzoate) (vegetable, phenol)81
  • Quercetin (flavonoid), (Ki: 33.4 µM)81
  • Resveratrol81
  • Sanggenone C (vegetable, phenol)81
  • Sanggenone D (vegetable, phenol)81
  • Scopoletin-7-O–D-(6-galloyl)-glucopyranoside (vegetable)81
  • Sulforaphane81
  • Tanshinon I (Tanshinon), (Ki: 26.3 µM)81
  • Tanshinone IIA (Tanshinone), (Ki: 6.89 µM) (strong)81
  • Tanshinone IIA sulfonate (Ki: 100 µM) (Tanshinone)
  • Δ⁹-tetrahydrocannabinol (cannabinoid), (Ki: 0.541 µM) (strong)81
  • Thioridazine (strong) (IC50: 7.0 µM)8711
  • Ursolic acid (triterpenoid), (Ki: 0.24 µM) (strong)81
  • Compound 12 (triterpenoid)
  • Compound 13 (triterpenoid)
  • Yangonin (Ki = 24.9 μM)88
8.3.3.3.1 CES1A1 inducers

A combination of methylphenidate and inducers causes a significant decrease in blood MPH.

  • Carmabazine is reported to be an inducer of CES1.87
  • Glucose (sugar)89
  • Phenobarbital (possible)87
  • Phenytoin (possible)87
  • Rifampin (possible)87
  • Sulforaphane compounds (antioxidant)81 Sulforaphane (4-methylsulfinylbutylisothiocyanate; 1-isothiocyanato-4-methylsulfinylbutane) is a dietary and plant phytochemical found in plants as a biologically inactive precursor
    • Sulforaphane is a strong CES1 inducer90
  • Trinitrobenzene sulfonate (strong)
    • Skin sensitizers, such as those used to test cosmetic products, can increase CES1 up to 20-fold91
  • Cinnamaldehyde (strong)
    • Skin sensitizers, such as those used to test cosmetic products, can increase CES1 up to 20-fold.91

  1. Rasmussen, Bjerre, Linnet, Jürgens, Dalhoff, Stefansson, Hankemeier, Kaddurah-Daouk, Taboureau, Brunak, Houmann, Jeppesen, Pagsberg, Plessen, Dyrborg, Hansen, Hansen, Hughes, Werge; INDICES Consortium (2015): Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics. Pharmacogenomics. 2015;16(6):649-65. doi: 10.2217/pgs.15.7. PMID: 25896426. REVIEW

  2. Elbe, Black, McGrane, Procyshyn (Hrsg.) (2019): Clinical Handbook of Psychotrophic Drugs for Children and Adolescents, 4th edition

  3. Masellis, Basile, Kennedy (2006): Neuropsychopharmacogenetics: ‘stimulating’ rationale therapy in attention-deficit/hyperactivity disorder (ADHD): pharmacogenetics of psychostimulants in ADHD. In: Gorwood, Hamon (editors): Psychopharmacogenetics. Boston: Springer US; 2006. p. 231 - 248.

  4. Stevens, Sangkuhl, Brown, Altman, Klein (2019): PharmGKB summary: methylphenidate pathway, pharmacokinetics/pharmacodynamics. Pharmacogenet Genomics. 2019 Aug;29(6):136-154. doi: 10.1097/FPC.0000000000000376. PMID: 30950912; PMCID: PMC6581573.

  5. Dinis-Oliveira (2017): Metabolomics of Methylphenidate and Ethylphenidate: Implications in Pharmacological and Toxicological Effects. Eur J Drug Metab Pharmacokinet. 2017 Feb;42(1):11-16. doi: 10.1007/s13318-016-0362-1. PMID: 27438788. REVIEW

  6. DeVane, Markowitz, Carson, Boulton, Gill, Nahas, Risch (2000): Single-dose pharmacokinetics of methylphenidate in CYP2D6 extensive and poor metabolizers. J Clin Psychopharmacol. 2000 Jun;20(3):347-9. doi: 10.1097/00004714-200006000-00009. PMID: 10831022.

  7. Walitza, Romanos, Renner, Gerlach (2016): Psychostimulanzien und andere Arzneistoffe, die zur Behandlung der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) angewendet werden. S. 289 bis 332, 323 in: Gerlach, Mehler-Wex, Walitza, Warnke, Wewetzer (Hrsg.) Neuro-/Psychopharmaka im Kindes- und Jugendalter, 3. Aufl.

  8. Sun, Murry, Sanghani, Davis, Kedishvili, Zou, Hurley, Bosron (2004): Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1. J Pharmacol Exp Ther. 2004 Aug;310(2):469-76. doi: 10.1124/jpet.104.067116. PMID: 15082749.

  9. Kutuk, Tufan, Topal, Acikbas, Guler, Karakas, Basaga, Kilicaslan, Altintas, Aka, Kutuk (2022): CYP450 2D6 and 2C19 genotypes in ADHD: not related with treatment resistance but with over-representation of 2C19 ultra-metabolizers. Drug Metab Pers Ther. 2022 Feb 24. doi: 10.1515/dmpt-2021-0163. PMID: 35218180.

  10. Kaddurah-Daouk, Hankemeier, Scholl, Baillie, Harms, Stage, Dalhoff, Jűrgens, Taboureau, Nzabonimpa, Motsinger-Reif, Thomsen, Linnet, Rasmussen; INDICES Consortium (2018): Pharmacometabolomics Research Network. Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate. CPT Pharmacometrics Syst Pharmacol. 2018 Aug;7(8):525-533. doi: 10.1002/psp4.12309. PMID: 30169917; PMCID: PMC6118295.)

  11. Childress, Komolova, Sallee (2019): An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019 Nov;15(11):937-974. doi: 10.1080/17425255.2019.1675636. PMID: 31581854.

  12. Her, Zhu (2020): Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators. Drug Metab Dispos. 2020 Mar;48(3):230-244. doi: 10.1124/dmd.119.089680. Erratum in: Drug Metab Dispos. 2020 Nov;48(11):1246. PMID: 31871135; PMCID: PMC7031766.

  13. Zhou L, Zhang C, Yang X, Liu L, Hu J, Hou Y, Tao H, Sugimura H, Chen Z, Wang L, Chen K (2021): Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1. Clin Transl Med. 2021 Jun;11(6):e449. doi: 10.1002/ctm2.449. PMID: 34185414; PMCID: PMC8181204.

  14. Lyauk, Stage, Bergmann, Ferrero-Milliani, Bjerre, Thomsen, Dalhoff, Rasmussen, Jürgens (2016): Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (CES1) Variants. Clin Transl Sci. 2016 Dec;9(6):337-345. doi: 10.1111/cts.12423. PMID: 27754602; PMCID: PMC5351003. n = 122

  15. Sai, Saito, Tatewaki, Hosokawa, Kaniwa, Nishimaki-Mogami, Naito, Sawada, Shirao, Hamaguchi, Yamamoto, Kunitoh, Tamura, Yamada, Ohe, Yoshida, Minami, Ohtsu, Matsumura, Saijo, Okuda (2010): Association of carboxylesterase 1A genotypes with irinotecan pharmacokinetics in Japanese cancer patients. Br J Clin Pharmacol. 2010 Aug;70(2):222-33. doi: 10.1111/j.1365-2125.2010.03695.x. PMID: 20653675; PMCID: PMC2911552.

  16. Suzaki, Uemura, Takada, Ohyama, Itohda, Morimoto, Imai, Hamasaki, Inano, Hosokawa, Tateishi, Ohashi (2013): The effect of carboxylesterase 1 (CES1) polymorphisms on the pharmacokinetics of oseltamivir in humans. Eur J Clin Pharmacol. 2013 Jan;69(1):21-30. doi: 10.1007/s00228-012-1315-5. PMID: 22673926.

  17. Brown JT, Beery N, Taran A, Stevens T, Henzler C, Badalamenti J, Regal R, McCarty CA (2023): Associations between CES1 variants and dosing and adverse effects in children taking methylphenidate. Front Pediatr. 2023 Jan 18;10:958622. doi: 10.3389/fped.2022.958622. PMID: 36741090; PMCID: PMC9890192.

  18. Stage, Jürgens, Guski, Thomsen, Bjerre, Ferrero-Miliani, Lyauk, Rasmussen, Dalhoff (2017): INDICES Consortium. The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects. Br J Clin Pharmacol. 2017 Jul;83(7):1506-1514. doi: 10.1111/bcp.13237. PMID: 28087982; PMCID: PMC5465325.

  19. Wang X, Shi J, Zhu HJ (2019): Functional Study of Carboxylesterase 1 Protein Isoforms. Proteomics. 2019 Feb;19(4):e1800288. doi: 10.1002/pmic.201800288. Epub 2019 Jan 25. PMID: 30520264; PMCID: PMC6377296.

  20. Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL, Malcolm R, Johnson JA, Youngblood GL, Sweet DH, Langaee TY, Markowitz JS (2008): Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet. 2008 Jun;82(6):1241-8. doi: 10.1016/j.ajhg.2008.04.015. PMID: 18485328; PMCID: PMC2427248.

  21. Stage, Jürgens, Guski, Thomsen, Bjerre, Ferrero-Miliani, Lyauk, Rasmussen, Dalhoff; INDICES Consortium (2017): The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects. Br J Clin Pharmacol. 2017 Jul;83(7):1506-1514. doi: 10.1111/bcp.13237. PMID: 28087982; PMCID: PMC5465325.

  22. Nemoda, Angyal, Tarnok, Gadoros, Sasvari-Szekely (2009): Carboxylesterase 1 gene polymorphism and methylphenidate response in ADHD. Neuropharmacology. 2009 Dec;57(7-8):731-3. doi: 10.1016/j.neuropharm.2009.08.014. PMID: 19733552. n = 173

  23. Stage, Dalhoff, Rasmussen, Schow Guski, Thomsen, Bjerre, Ferrero-Miliani, Busk Madsen, Jürgens (2019): The impact of human CES1 genetic variation on enzyme activity assessed by ritalinic acid/methylphenidate ratios. Basic Clin Pharmacol Toxicol. 2019 Jul;125(1):54-61. doi: 10.1111/bcpt.13212. PMID: 30801959.

  24. Xiao J, Shi J, Thompson BR, Smith DE, Zhang T, Zhu HJ (2022): Physiologically-Based Pharmacokinetic Modeling to Predict Methylphenidate Exposure Affected by Interplay Among Carboxylesterase 1 Pharmacogenetics, Drug-Drug Interactions, and Sex. J Pharm Sci. 2022 Sep;111(9):2606-2613. doi: 10.1016/j.xphs.2022.04.019. PMID: 35526575; PMCID: PMC9391289.

  25. Orcholski, Khurshudyan, Shamskhou, Yuan, Chen, Kodani, Morisseau, Hammock, Hong, Alexandrova, Alastalo, Berry, Zamanian, de Jesus Perez (2017): Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. 2017 Aug 1;313(2):L252-L266. doi: 10.1152/ajplung.00453.2016. PMID: 28473326; PMCID: PMC5582936.

  26. Wang X, Wang G, Shi J, Aa J, Comas R, Liang Y, Zhu HJ (2016): CES1 genetic variation affects the activation of angiotensin-converting enzyme inhibitors. Pharmacogenomics J. 2016 Jun;16(3):220-30. doi: 10.1038/tpj.2015.42. PMID: 26076923; PMCID: PMC6329299.

  27. Oh, Lee, Lee, Cho, Yoon, Jang, Yu, Lim (2017): The novel carboxylesterase 1 variant c.662A>G may decrease the bioactivation of oseltamivir in humans. PLoS One. 2017 Apr 24;12(4):e0176320. doi: 10.1371/journal.pone.0176320. PMID: 28437488; PMCID: PMC5402961.

  28. Xiao, Luo, Liu, Chen, Cao, Liu, Zhou, Zhou, Zhang (2017): Effect of carboxylesterase 1 S75N on clopidogrel therapy among acute coronary syndrome patients. Sci Rep. 2017 Aug 3;7(1):7244. doi: 10.1038/s41598-017-07736-1. PMID: 28775293; PMCID: PMC5543069. n = 851

  29. Johnson, Barry, Lambert, Fitzgerald, McNicholas, Kirley, Gill, Bellgrove, Hawi (2013): Methylphenidate side effect profile is influenced by genetic variation in the attention-deficit/hyperactivity disorder-associated CES1 gene. J Child Adolesc Psychopharmacol. 2013 Dec;23(10):655-64. doi: 10.1089/cap.2013.0032. PMID: 24350812. n = 77, davon 72 A/G und 4 G/G

  30. Johnson, Barry, Lambert, Fitzgerald, McNicholas, Kirley, Gill, Bellgrove, Hawi (2013): Methylphenidate side effect profile is influenced by genetic variation in the attention-deficit/hyperactivity disorder-associated CES1 gene. J Child Adolesc Psychopharmacol. 2013 Dec;23(10):655-64. doi: 10.1089/cap.2013.0032. PMID: 24350812. n = 77, davon 60 C/C und 15 C/G

  31. Johnson, Barry, Lambert, Fitzgerald, McNicholas, Kirley, Gill, Bellgrove, Hawi (2013): Methylphenidate side effect profile is influenced by genetic variation in the attention-deficit/hyperactivity disorder-associated CES1 gene. J Child Adolesc Psychopharmacol. 2013 Dec;23(10):655-64. doi: 10.1089/cap.2013.0032. PMID: 24350812. n = 77, davon 70 T/T und 5 C/T

  32. Johnson, Barry, Lambert, Fitzgerald, McNicholas, Kirley, Gill, Bellgrove, Hawi (2013): Methylphenidate side effect profile is influenced by genetic variation in the attention-deficit/hyperactivity disorder-associated CES1 gene. J Child Adolesc Psychopharmacol. 2013 Dec;23(10):655-64. doi: 10.1089/cap.2013.0032. PMID: 24350812. n = 77, davon 51 A/A und 22 A/C und C/C

  33. Hernandez MH, Bote V, Serra-LLovich A, Cendros M, Salazar J, Mestres C, Guijarro S, Alvarez A, Lamborena C, Mendez I, Sanchez B, Hervas A, Arranz MJ (2022): CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders. Pharmgenomics Pers Med. 2022 Nov 8;15:951-957. doi: 10.2147/PGPM.S377210. PMID: 36393977; PMCID: PMC9653043.

  34. Johnson, Barry, Lambert, Fitzgerald, McNicholas, Kirley, Gill, Bellgrove, Hawi (2013): Methylphenidate side effect profile is influenced by genetic variation in the attention-deficit/hyperactivity disorder-associated CES1 gene. J Child Adolesc Psychopharmacol. 2013 Dec;23(10):655-64. doi: 10.1089/cap.2013.0032. PMID: 24350812. n = 77, davon 52 G/G und 24 C/G und C/C

  35. Johnson, Barry, Lambert, Fitzgerald, McNicholas, Kirley, Gill, Bellgrove, Hawi (2013): Methylphenidate side effect profile is influenced by genetic variation in the attention-deficit/hyperactivity disorder-associated CES1 gene. J Child Adolesc Psychopharmacol. 2013 Dec;23(10):655-64. doi: 10.1089/cap.2013.0032. PMID: 24350812. n = 77, davon 52 C/C und 23 C/T und T/T

  36. Johnson, Barry, Lambert, Fitzgerald, McNicholas, Kirley, Gill, Bellgrove, Hawi (2013): Methylphenidate side effect profile is influenced by genetic variation in the attention-deficit/hyperactivity disorder-associated CES1 gene. J Child Adolesc Psychopharmacol. 2013 Dec;23(10):655-64. doi: 10.1089/cap.2013.0032. PMID: 24350812. n = 77, davon 37 A/A und 39 A/G und G/G

  37. Bruxel, Salatino-Oliveira, Genro, Zeni, Polanczyk, Chazan, Rohde, Hutz (2013): Association of a carboxylesterase 1 polymorphism with appetite reduction in children and adolescents with attention-deficit/hyperactivity disorder treated with methylphenidate. Pharmacogenomics J. 2013 Oct;13(5):476-80. doi: 10.1038/tpj.2012.25. PMID: 22688218.

  38. Pagerols, Richarte, Sánchez-Mora, Garcia-Martínez, Corrales, Corominas, Cormand, Casas, Ribasés, Ramos-Quiroga (2017): Pharmacogenetics of methylphenidate response and tolerability in attention-deficit/hyperactivity disorder. Pharmacogenomics J. 2017 Jan;17(1):98-104. doi: 10.1038/tpj.2015.89. PMID: 26810137.

  39. Manor, Laiba, Eisenberg, Meidad, Lerer, Israel, Gritsenko, Tyano, Faraone, Ebstein (2008): Association between tryptophan hydroxylase 2, performance on a continuance performance test and response to methylphenidate in ADHD participants. Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1501-8. doi: 10.1002/ajmg.b.30702. PMID: 18213624.

  40. Guimarães, Zeni, Polanczyk, Genro, Roman, Rohde, Hutz (2009): MAOA is associated with methylphenidate improvement of oppositional symptoms in boys with attention deficit hyperactivity disorder. Int J Neuropsychopharmacol. 2009 Jun;12(5):709-14. doi: 10.1017/S146114570900021 PMID: 19309535.

  41. Manor, Tyano, Mel, Eisenberg, Bachner-Melman, Kotler, Ebstein (2002): Family-based and association studies of monoamine oxidase A and attention deficit hyperactivity disorder (ADHD): preferential transmission of the long promoter-region repeat and its association with impaired performance on a continuous performance test (TOVA). Mol Psychiatry. 2002;7(6):626-32. doi: 10.1038/sj.mp.4001037. PMID: 12140786.

  42. Kereszturi, Tarnok, Bognar, Lakatos, Farkas, Gadoros, Sasvari-Szekely, Nemoda (2008): Catechol-O-methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children. Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1431-5. doi: 10.1002/ajmg.b.30704. PMID: 18214865.

  43. Cheon, Jun, Cho (2008): Association of the catechol-O-methyltransferase polymorphism with methylphenidate response in a classroom setting in children with attention-deficit hyperactivity disorder. Int Clin Psychopharmacol. 2008 Sep;23(5):291-8. doi: 10.1097/YIC.0b013e328306a977. PMID: 18703939.

  44. Myer, Boland, Faraone (2018): Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD. Mol Psychiatry. 2018 Sep;23(9):1929-1936. doi: 10.1038/mp.2017.234. PMID: 29230023; PMCID: PMC7039663.

  45. McGough, McCracken, Loo, Manganiello, Leung, Tietjens, Trinh, Baweja, Suddath, Smalley, Hellemann, Sugar (2009): A candidate gene analysis of methylphenidate response in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2009 Dec;48(12):1155-64. doi: 10.1097/CHI.0b013e3181bc72e3. PMID: 19858760; PMCID: PMC2888980.

  46. Green, Weinberger, Diamond, Berant, Hirschfeld, Frisch, Zarchi, Weizman, Gothelf (2011): The effect of methylphenidate on prefrontal cognitive functioning, inattention, and hyperactivity in velocardiofacial syndrome. J Child Adolesc Psychopharmacol. 2011 Dec;21(6):589-95. doi: 10.1089/cap.2011.0042. PMID: 22149470.

  47. Terrillion CE, Dao DT, Cachope R, Lobo MK, Puche AC, Cheer JF, Gould TD (2017): Reduced levels of Cacna1c attenuate mesolimbic dopamine system function. Genes Brain Behav. 2017 Jun;16(5):495-505. doi: 10.1111/gbb.12371. PMID: 28186690; PMCID: PMC5457318.

  48. Kim, Kim, Hong, Cho, Shin, Yoo (2010): Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder. Behav Brain Funct. 2010 Oct 7;6:57. doi: 10.1186/1744-9081-6-57. PMID: 20929549; PMCID: PMC2959002.

  49. Park, Kim, Yang, Hong, Park, Kim, Shin, Yoo, Cho (2012): Possible effect of norepinephrine transporter polymorphisms on methylphenidate-induced changes in neuropsychological function in attention-deficit hyperactivity disorder. Behav Brain Funct. 2012 May 16;8:22. doi: 10.1186/1744-9081-8-22. PMID: 22591463; PMCID: PMC3508798.

  50. Hong, Kim, Cho, Shin, Kim, Yoo (2012): Dopaminergic and noradrenergic gene polymorphisms and response to methylphenidate in korean children with attention-deficit/hyperactivity disorder: is there an interaction? J Child Adolesc Psychopharmacol. 2012 Oct;22(5):343-52. doi: 10.1089/cap.2011.0076. PMID: 23083021.

  51. Cho, Kim, Cummins, Kim, Bellgrove (2012): Norepinephrine transporter -3081(A/T) and alpha-2A-adrenergic receptor MspI polymorphisms are associated with cardiovascular side effects of OROS-methylphenidate treatment. J Psychopharmacol. 2012 Mar;26(3):380-9. doi: 10.1177/0269881111405356. PMID: 21628343.

  52. Yang, Wang, Li, Faraone (2004): Association of norepinephrine transporter gene with methylphenidate response. J Am Acad Child Adolesc Psychiatry. 2004 Sep;43(9):1154-8. doi: 10.1097/01.chi.0000131134.63368.46. PMID: 15322419.

  53. Song, Song, Jhung, Cheon (2011): Norepinephrine transporter gene (SLC6A2) is involved with methylphenidate response in Korean children with attention deficit hyperactivity disorder. Int Clin Psychopharmacol. 2011 Mar;26(2):107-13. doi: 10.1097/YIC.0b013e32834152d1. PMID: 21127421.

  54. Froehlich, Epstein, Nick, Melguizo Castro, Stein, Brinkman, Graham, Langberg, Kahn (2011); Pharmacogenetic predictors of methylphenidate dose-response in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011 Nov;50(11):1129-1139.e2. doi: 10.1016/j.jaac.2011.08.002. PMID: 22024001; PMCID: PMC3225067.

  55. Leddy, Waxmonsky, Salis, Paluch, Gnagy, Mahaney, Erbe, Pelham, Epstein (2009): Dopamine-related genotypes and the dose-response effect of methylphenidate on eating in attention-deficit/hyperactivity disorder youths. J Child Adolesc Psychopharmacol. 2009 Apr;19(2):127-36. doi: 10.1089/cap.2008.046. PMID: 19364291.

  56. Stein, Waldman, Newcorn, Bishop, Kittles, Cook (2014): Dopamine transporter genotype and stimulant dose-response in youth with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2014 Jun;24(5):238-44. doi: 10.1089/cap.2013.0102. PMID: 24813374; PMCID: PMC4064733.

  57. Pasini, Sinibaldi, Paloscia, Douzgou, Pitzianti, Romeo, Curatolo, Pizzuti (2013): Neurocognitive effects of methylphenidate on ADHD children with different DAT genotypes: a longitudinal open label trial. Eur J Paediatr Neurol. 2013 Jul;17(4):407-14. doi: 10.1016/j.ejpn.2013.02.002. PMID: 23541676.

  58. Kambeitz, Romanos, Ettinger (2013): Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD. Pharmacogenomics J. 2014 Feb;14(1):77-84. doi: 10.1038/tpj.2013.9. PMID: 23588108.

  59. Gomez-SanchezI, Carballo, Riveiro-Alvarez, Soto-Insuga, Rodrigo, Mahillo-Fernandez, Abad-Santos, Dal-Ré, Ayuso (2017): Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects. Sci Rep. 2017 Sep 4;7(1):10391. doi: 10.1038/s41598-017-10912-y. PMID: 28871191; PMCID: PMC5583388.

  60. Seeger, Schloss, Schmidt (2001): Marker gene polymorphisms in hyperkinetic disorder–predictors of clinical response to treatment with methylphenidate? Neurosci Lett. 2001 Nov 2;313(1-2):45-8. doi: 10.1016/s0304-3940(01)02253-4. PMID: 11684336.

  61. Park, Kim, Cheon (2015): Association Between 5-HTTLPR Polymorphism and Tics after Treatment with Methylphenidate in Korean Children with Attention-Deficit/Hyperactivity Disorder. J Child Adolesc Psychopharmacol. 2015 Oct;25(8):633-40. doi: 10.1089/cap.2014.0168. PMID: 26402385; PMCID: PMC4615776.

  62. McCracken, Badashova, Posey, Aman, Scahill, Tierney, Arnold, Vitiello, Whelan, Chuang, Davies, Shah, McDougle, Nurmi (2014): Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders. Pharmacogenomics J. 2014 Jun;14(3):295-302. doi: 10.1038/tpj.2013.23. PMID: 23856854; PMCID: PMC4034115.

  63. Cheon, Kim, Cho (2007): Association of 4-repeat allele of the dopamine D4 receptor gene exon III polymorphism and response to methylphenidate treatment in Korean ADHD children. Neuropsychopharmacology. 2007 Jun;32(6):1377-83. doi: 10.1038/sj.npp.1301244. Erratum in: Neuropsychopharmacology. 2007 Jun;32(6):1431. PMID: 17077808.

  64. Tahir, Yazgan, Cirakoglu, Ozbay, Waldman, Asherson (2000): Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. Mol Psychiatry. 2000 Jul;5(4):396-404. doi: 10.1038/sj.mp.4000744. PMID: 10889550.

  65. Hamarman, Fossella, Ulger, Brimacombe, Dermody (2004): Dopamine receptor 4 (DRD4) 7-repeat allele predicts methylphenidate dose response in children with attention deficit hyperactivity disorder: a pharmacogenetic study. J Child Adolesc Psychopharmacol. 2004 Winter;14(4):564-74. doi: 10.1089/cap.2004.14.564. PMID: 15662148.

  66. McGough, McCracken, Swanson, Riddle, Kollins, Greenhill, Abikoff, Davies, Chuang, Wigal, Wigal, Posner, Skrobala, Kastelic, Ghuman, Cunningham, Shigawa, Moyzis, Vitiello (2006): Pharmacogenetics of methylphenidate response in preschoolers with ADHD. J Am Acad Child Adolesc Psychiatry. 2006 Nov;45(11):1314-1322. doi: 10.1097/01.chi.0000235083.40285.08. PMID: 17023870.

  67. Polanczyk, Zeni, Genro, Guimarães, Roman, Hutz, Rohde (2007): Association of the adrenergic alpha2A receptor gene with methylphenidate improvement of inattentive symptoms in children and adolescents with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2007 Feb;64(2):218-24. doi: 10.1001/archpsyc.64.2.218. PMID: 17283289.

  68. da Silva, Pianca, Roman, Hutz, Faraone, Schmitz, Rohde (2008): Adrenergic alpha2A receptor gene and response to methylphenidate in attention-deficit/hyperactivity disorder-predominantly inattentive type. J Neural Transm (Vienna). 2008;115(2):341-5. doi: 10.1007/s00702-007-0835-0. PMID: 18200436.

  69. Cheon, Cho, Koo, Song, Namkoong (2009): Association between homozygosity of a G allele of the alpha-2a-adrenergic receptor gene and methylphenidate response in Korean children and adolescents with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2009 Apr 1;65(7):564-70. doi: 10.1016/j.biopsych.2008.12.003. PMID: 19150055.

  70. Song, Kim, Hong, Lee, Lee, Choi, Lee, Yook (2014): Association of SNAP-25, SLC6A2, and LPHN3 with OROS methylphenidate treatment response in attention-deficit/hyperactivity disorder. Clin Neuropharmacol. 2014 Sep-Oct;37(5):136-41. doi: 10.1097/WNF.0000000000000045. PMID: 25229170.

  71. Choudhry, Sengupta, Grizenko, Fortier, Thakur, Bellingham, Joober (2012): LPHN3 and attention-deficit/hyperactivity disorder: interaction with maternal stress during pregnancy. J Child Psychol Psychiatry. 2012 Aug;53(8):892-902. doi: 10.1111/j.1469-7610.2012.02551.x. PMID: 22486528.

  72. Labbe, Liu, Atherton, Gizenko, Fortier, Sengupta, Ridha (2012): Refining psychiatric phenotypes for response to treatment: contribution of LPHN3 in ADHD. Am J Med Genet B Neuropsychiatr Genet. 2012 Oct;159B(7):776-85. doi: 10.1002/ajmg.b.32083. PMID: 22851411.

  73. Bruxel, Salatino-Oliveira, Akutagava-Martins, Tovo-Rodrigues, Genro, Zeni, Polanczyk, Chazan, Schmitz, Arcos-Burgos, Rohde, Hutz (2015): LPHN3 and attention-deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study. Genes Brain Behav. 2015 Jun;14(5):419-27. doi: 10.1111/gbb.12224. PMID: 25989180.

  74. Kim, Cummins, Kim, Bellgrove, Hong, Song, Shin, Cho, Kim, Son, Shin, Chung, Han (2011): Val/Val genotype of brain-derived neurotrophic factor (BDNF) Val⁶⁶Met polymorphism is associated with a better response to OROS-MPH in Korean ADHD children. Int J Neuropsychopharmacol. 2011 Nov;14(10):1399-410. doi: 10.1017/S146114571100099X. PMID: 21733227.

  75. Park, Kim, Kim, Shin, Cho, Kim, Son, Shin, Chung, Han (2014): Neurotrophin 3 genotype and emotional adverse effects of osmotic-release oral system methylphenidate (OROS-MPH) in children with attention-deficit/hyperactivity disorder. J Psychopharmacol. 2014 Mar;28(3):220-6. doi: 10.1177/0269881113480989. PMID: 23471121.

  76. Park, Kim, Cho, Kim, Kim, Shin, Yoo, Han, Cheong (2014): The metabotropic glutamate receptor subtype 7 rs3792452 polymorphism is associated with the response to methylphenidate in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2014 May;24(4):223-7. doi: 10.1089/cap.2013.0079. PMID: 24815731.

  77. Kim, Kim, Park, Park, Hong, Han, Cheong, Choi, Lee, Kim (2017): Association of the GRIN2B rs2284411 polymorphism with methylphenidate response in attention-deficit/hyperactivity disorder. J Psychopharmacol. 2017 Aug;31(8):1070-1077. doi: 10.1177/0269881116667707. PMID: 27624150.

  78. Shumay, Wiers, Shokri-Kojori, Kim, Hodgkinson, Sun, Tomasi, Wong, Weinberger, Wang, Fowler, Volkow (2017): New Repeat Polymorphism in the AKT1 Gene Predicts Striatal Dopamine D2/D3 Receptor Availability and Stimulant-Induced Dopamine Release in the Healthy Human Brain. J Neurosci. 2017 May 10;37(19):4982-4991. doi: 10.1523/JNEUROSCI.3155-16.2017. Erratum in: J Neurosci. 2017 Aug 16;37(33):8043. PMID: 28416594; PMCID: PMC5426185.

  79. Chatterjee, Saha, Maitra, Ray, Sinha, Mukhopadhyay (2022): Post-treatment symptomatic improvement of the eastern Indian ADHD probands is influenced by CYP2D6 genetic variations. Drug Metab Pers Ther. 2022 Sep 28. doi: 10.1515/dmpt-2022-0120. PMID: 36169235.

  80. Busti (2015): The Inhibitory Constant (Ki) and its Use in Understanding Drug Interactions

  81. Xu J, Qiu JC, Ji X, Guo HL, Wang X, Zhang B, Wang T, Chen F (2019): Potential Pharmacokinetic Herb-Drug Interactions: Have we Overlooked the Importance of Human Carboxylesterases 1 and 2? Curr Drug Metab. 2019;20(2):130-137. doi: 10.2174/1389200219666180330124050. PMID: 29600756. REVIEW

  82. Merali, Ross, Paré (2014): The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect. Drug Metabol Drug Interact. 2014;29(3):143-51. doi: 10.1515/dmdi-2014-0009. PMID: 24988246.

  83. Crow, Herring, Xie, Borazjani, Potter, Ross (2010): Inhibition of carboxylesterase activity of THP1 monocytes/macrophages and recombinant human carboxylesterase 1 by oxysterols and fatty acids. Biochim Biophys Acta. 2010 Jan;1801(1):31-41. doi: 10.1016/j.bbalip.2009.09.002. PMID: 19761868; PMCID: PMC2787731.

  84. Patrick, Straughn, Minhinnett, Yeatts, Herrin, DeVane, Malcolm, Janis, Markowitz (2007): Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2007 Mar;81(3):346-53. doi: 10.1038/sj.clpt.6100082. PMID: 17339864; PMCID: PMC3188424.

  85. Markowitz, Logan, Diamond, Patrick (1999): Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion. J Clin Psychopharmacol. 1999 Aug;19(4):362-6. doi: 10.1097/00004714-199908000-00013. PMID: 10440465.

  86. Williard, Middaugh, Zhu, Patrick (2007): Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity. Behav Pharmacol. 2007 Feb;18(1):39-51. doi: 10.1097/FBP.0b013e3280143226. PMID: 17218796.

  87. Jaeschke, Sujkowska, Sowa-Kućma (2021): Methylphenidate for attention-deficit/hyperactivity disorder in adults: a narrative review. Psychopharmacology (Berl). 2021 Oct;238(10):2667-2691. doi: 10.1007/s00213-021-05946-0. PMID: 34436651; PMCID: PMC8455398. REVIEW

  88. Melchert PW, Qian Y, Zhang Q, Klee BO, Xing C, Markowitz JS (2022): In vitro inhibition of carboxylesterase 1 by Kava (Piper methysticum) Kavalactones. Chem Biol Interact. 2022 Apr 25;357:109883. doi: 10.1016/j.cbi.2022.109883. PMID: 35278473; PMCID: PMC9244838.

  89. Xu J, Yin L, Xu Y, Li Y, Zalzala M, Cheng G, Zhang Y (2014): Hepatic carboxylesterase 1 is induced by glucose and regulates postprandial glucose levels. PLoS One. 2014 Oct 6;9(10):e109663. doi: 10.1371/journal.pone.0109663. PMID: 25285996; PMCID: PMC4186840.

  90. Chen YT, Shi D, Yang D, Yan B (2012): Antioxidant sulforaphane and sensitizer trinitrobenzene sulfonate induce carboxylesterase-1 through a novel element transactivated by nuclear factor-E2 related factor-2. Biochem Pharmacol. 2012 Sep 15;84(6):864-71. doi: 10.1016/j.bcp.2012.06.025. PMID: 22776248; PMCID: PMC4096214.

  91. Python, Goebel, Aeby (2009): Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83. doi: 10.1016/j.taap.2009.06.003. PMID: 19524605.

Diese Seite wurde am 13.03.2023 zuletzt aktualisiert.