CES1 Metabolizing enzyme

• 8.3.3. CES1
  • 8.3.3.1. Non-genetic factors affecting CES1 metabolism
  • 8.3.3.2. Genetic influences affecting CES1 metabolism
    • 8.3.3.2.1. CES1 haplotypes, hybrid genes
    • 8.3.3.2.2. Neurotransmitter synthesis and degradation
    • 8.3.3.2.3. Neurotransmitter reuptake transporter genes
    • 8.3.3.2.4. Receptor genes
    • 8.3.3.2.5. Neurotransmitter release
    • 8.3.3.2.6. Neuronal plasticity and synaptic effectors
    • 8.3.3.2.7. Downstream neurotransmitter effects
    • 8.3.3.2.8. CYP2D6 -gene variants influence effect of MPH and ATX
  • 8.3.3.3. CES1: Substrates/Inhibitors/Inductors
    • 8.3.3.3.1 CES1 substrates
    • 8.3.3.3.2 CES1A1 inhibitors
    • 8.3.3.3.1 CES1A1 inducers

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1A1 (CES1) in the liver.² The earlier assumption that MPH is metabolized by hepatic lysozyme enzymes is outdated.³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