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MPH part 3: degradation, potency

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MPH part 3: degradation, potency

13. Methylphenidate degradation

13.1. Degradation pathways of methylphenidate

  • (primarily) carboxylesterase 1A1 (CES1) in the liver to ritalic acid (aphenyl-2-piperidine acetic acid).1 The earlier assumption that MPH is metabolized by hepatic lysozyme enzymes is outdated.2
    CES1 predominantly degrades L-MPH, less degrades d-MPH. Therefore, more d-MPH (dexmethylphenidate) remains in the plasma. Most MPH preparations contain a racemic mixture of d- and L-MPH, with only d-MPH being pharmacologically active.3 60 to 80% of the ingested MPH is excreted in the urine as ritalinic acid.4
  • aromatic hydroxylation to p-hydroxy-methylphenidate (p-hydroxy-MPH)3 share between 1.5 and 12 % of the degradation.
  • microsomal oxidation 6-oxo-methylphenidate (6-oxo-MPH; inactive metabolite)3 fraction to 2.5% of MPH.
  • unchanged excretion of MPH is reported to be less than 1%4 to with urine: 2%, in feces: 3%3

CYP enzymes are not involved in the degradation of MPH.567 Therefore, there is a relatively low risk of drug interactions.2

MPH unretarded has a blood plasma half-life of 2 to 3 hours8, 2.9 hours.1 The blood plasma half-life of sustained-release MPH available in Europe varies between 3 and 4 hours depending on the preparation.1

The activity of CES1 is highly variable. What contributes to this variability is largely unknown.9
The bioavailability of MPH in children ranges from 11 to 53%.4

13.2. Carboxylesterase 1 (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:10

  • Cholesterol esters
  • Triglycerides
  • bioactive lipids

13.1.1. Degradation by CES1

CES1 is critical for the degradation of various drugs listed below.11

13.1.1.1. Active ingredients for the central nervous system
  • Methylphenidate
  • Cocaine
  • Heroin
  • Mepridine
  • Flumazenil
  • Rufinamide
  • Amphetamines12
    • METH
    • Albeit predominantly through P450 2D6 (CYP2D6)
13.1.1.2. Antihyperlipidemics
  • Clofibrate
  • Fenofibrate
13.1.1.3. Adrenal glucocorticoids
  • Ciclesonide
13.1.1.4. Endogenous compounds
  • Cholesterol
  • Fatty acid ethyl ester
13.1.1.5. ACE inhibitors
  • Enalapril
  • Imidapril13
  • Benzapril
  • Quinapril
  • Ramipril
  • Trandolapril
13.1.1.6. Antiviral agents
  • Oseltamivir13
  • Sofosbuvir
  • Tenofoviralafenamide
13.1.1.7. Angiotensin Receptor Neprilysin Inhibitor (ARNi)
  • Sacubitril
13.1.1.8. Cancer Drugs
  • Capecitabine
  • Irinotecan
  • Telotristat etiprate
13.1.1.9. Antiplatelet/anticoagulants
  • Clopidogrel13
  • Dabigatran exilate13
13.1.1.10. Immunosuppressive agents
  • Mycophenolate mofetil
13.1.1.11. Pesticides
  • Trans-Permethrin
  • Para-nitrophenyl valerate
13.1.1.12. Other
  • Dimethyl fumarate (MS agent)
  • Oxybutynin (anticholinergic; used, among other things, for urinary incontinence)
13.1.1.13. Chemical warfare agents
  • Sarin
  • Soman
  • Tabun
13.1.1.14. CES1A1 inhibitors

Strong CES1A1 inhibitors include:14

  • Aripiprazole (IC50: 5.7 µM)15
  • Fluoxetine (IC50: 6.1 µM)15
  • Thioridazine (IC50: 7.0 µM)15
  • Perphenazine (IC50: 13.9 µM)15
  • Alcohol16

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.

13.1.1.15. CES1 inducers

Carmabazine is reported to be an inducer of CES1.15
Further inducers to be considered are:15

  • Phenobarbital
  • Phenytoin
  • Rifampin

A combination of methylphenidate and inducers are reported to result in a significant decrease in blood MPH

We question whether the cases of MPH superfast metabolizers that are sometimes observed in practice (unretarded MPH acting for only 1 hour instead of 2.5-3.5 hours, retarded MPH acting for 2-3 hours instead of 5-6 hours) may be due to such drug combinations.

14. Influences on the potency of MPH

14.1. CES1 affects rate of metabolism of MPH

There are large individual differences in the response to many drugs metabolized by CES1.10 The expression and activity of CES1 vary 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.14 Factors affecting degradation by CES1 include:11

14.1.1. Non-genetic factors affecting CES1 metabolism

  • Development status
  • Gender
  • Drug interactions
    • Alcohol
      • potent CES1 inhibitor
      • In case of simultaneous intake of alcohol and MPH:16
        • increases the MPH concentration in humans
        • alcohol inhibits CES1-mediated MPH degradation by catalyzing MPH to ethylphenidate1417
          • more l-ethylphenidate (pharmacologically ineffective) seems to be produced than d-ethylphenidate18
          • Ethylphenidate appears to be toxic
          • Ethylphenidate correlates with significantly higher plasma d-MPH levels and enhanced euphoric effects14
          • Ethylphenidate binds similarly strongly to DAT but less strongly to NET than MPH18
    • Fatty acids inhibit CES119
      • especially unsaturated fatty acids
      • potent CES1 inhibitors:
        • 27-hydroxycholesterol (27-HC) (IC50=33 nM)
        • Arachidonic acid
          • strongest fatty acid inhibitor of recombinant CES1
          • acted by a non-competitive mechanism (Kiapp=1.7 μM)
      • moderate CES1 inhibitors:
        • 24(S),25-Epoxycholesterol (IC50=8.1 μM);
      • weak CES1 inhibitors:
        • Cholesterol
        • 7-Ketocholesterol
        • 22(R)-hydroxycholesterol
        • 24(S)-hydroxycholesterol
        • 25-hydroxycholesterol
      • partially non-competitive inhibitor
        • 27-Hydroxycholesterol (Kiapp=10 nM)
          • impaired intracellular CES1 activity after treatment of intact THP1 cells
      • Oxysterol
        • Cholesterol metabolite; also inhibits CES1

14.2. Genetic influences

14.2.1. Genetic factors influencing CES1 metabolism

14.2.1.1. Haplotypes, hybrid genes

Two haplotypes of CES1 are known:1039

  • 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)

Therefore, some individuals carry two almost identical CES1 copies on the same chromosome.10

Hybrid gene variants are:

  • CES1P1 with CES1
    • higher transcriptional activity than CES1P1
  • CES1A2 (further hybrid gene variant from CES1 and CES1P1
    • has 2% of the transcriptional efficiency of CES1
  • CES1A1b
  • CES1A1c (CES1VAR)
    • has no noticeable effect on the metabolism of drugs9

CES1 gene variants with functional effects are rare. The major factors affecting CES1 metabolism appear to depend on other influences.9

To date, nearly 200 variants have been found in the CES1 / CES1P1 gene region.10

  • genetic polymorphisms
    • Single nucleotide polymorphisms (SNPs)
      • G143E (rs71647871) deactivates CES1
        • G143E subjects required less MPH,9 20 in one study it was 28% less21 with up to 50% higher d-MPH levels observed at the same dose of MPH.
      • rs115629050 decreases CES112
        • here, an increased metabolization of MPH and thus a lower dosage requirement should be expected
      • E220G (c.662A>G, rs200707504) is reported to be associated with decreased CES1 activity22
      • p.Gly143Glu (rs71647871) appears to significantly impair the metabolism of:10
        • Methylphenidate
        • Trandolapril
        • Oseltamivir
      • c.428G>A (p.Gly143Glu, rs121912777) is reported to be associated with decreased CES1 activity22
      • c.780delT (p.Asp260fs, rs71647872) is reported to be associated with decreased CES1 activity22
      • c56G>T (rs3826190) is reported to be associated with decreased CES1 activity22
      • c.808G>T (rs115629050) is reported to be associated with decreased CES1 activity22
      • S75N (rs2307240)
        • appears to increase the activity of CES1 in relation to clopidogrel23
        • does not appear to affect CES1 activity in relation to methylphenidate in children24
      • rs3815589
        • does not appear to affect CES1 activity in relation to methylphenidate in children25
      • rs2287194
        • does not appear to affect CES1 activity in relation to methylphenidate in children26
      • rs2244613
        • does not appear to affect CES1 activity in relation to methylphenidate in children27
        • correlated significantly with sadness as a side effect of unretarded MPH in A/A subjects
      • rs2002577
        • does not appear to affect CES1 activity in relation to methylphenidate in children28
        • 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 children29
      • rs12443580
        • does not appear to affect CES1 activity in relation to methylphenidate in children30
      • 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.31
      • different CES1A2 promoter haplotypes are reported to be associated with increased CES1 expression:10
        • 47C,
        • 46T
        • 41G
        • 40
        • 37C
        • 34G
        • 32T
    • Copy number variants3
      • 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)
      • 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.

14.2.2. Further gene influences on effect of MPH

Stevens et al compiled studies that addressed influences of gene variants on the effects of MPH:3

14.2.2.1. Neurotransmitter synthesis and degradation
  • TH gene32
    • Rs2070762 C/C: Decreased response (CGI-I)
  • DBH gene32
    • 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 gene32
    • 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 gene33
    • 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)34
    • 30-bp promoter VNTR 4- and 5-repeat alleles Improved values for impulsivity (TOVA)35
  • COMT
    • Rs4680 c/G
      • Increased response rate (ADHD-RS, CGI-S)36, (K-ARS)37, (metastudy)38
      • Increased irritability39
    • Rs4680 G: Increased sadness40
14.2.2.2. Neurotransmitter reuptake transporter genes
  • SLC6A2 - noradrenaline transporter gene

    • Rs28386840 A/A Reduced response (CGI-I)41
    • Rs28386840 A/A Reduced response (TOVA)42
    • Rs28386840 A/A Reduced response (ADHD-RS and CGI-I)43
    • Rs28386840 T Enhanced response (metastudy)38
    • Rs28386840 T/T Increased HR44
    • Rs5569 G Increased response (ADHD-RS)45
    • Rs5569 G/G Increased response (ADHD-RS and CGI-S)46
    • Rs5569 G/G Increased response (TOVA)42
    • Rs5569 N/A Increased response (metastudy)38
  • SLC6A3 - Dopamine transporter gene

    • Rs28363170 absence of 10R alleles
      • Improved hyperactive-impulsive scores (Vanderbilt ADHD Parent and Teacher Rating Scales)47
      • DAT 9/9: stronger response to MPH than 9/10 and 10/1048
      • 9R/9R: Reduced Response (ADHD-RS)49
      • 10R/10R: Improvements in working memory (N-Back Test)50
      • 10R/10R: Reduced response (meta-analysis, naturalistic studies)51
      • 10R/10R: Reduced response (metastudy)38
    • Rs2550948 G: Amplified response (CGI-S)52
  • SLC6A4 - Serotonin transporter gene

    • 5HTTLPR L/L (i.e., DRD4 7R carriers) Minor symptom improvement (CGAS)53
    • 5HTTLPR L Lower math values (PERMP)39
    • 5HTTLPR L/L Decreasing vegetative symptoms (sleep problems and loss of appetite)39
    • 5HTTLPR L Increased nail biting54
    • 5HTTLPR L Increased tics54
    • 17-bp VNTR Lack of 12R allele Minor symptom improvement (ADHD-RS)39
    • 17-bp VNTR 12R/12R Decreased response rate (CGI-I and ABC subscale for hyperactivity)55
14.2.2.3. Receptor genes
  • DRD1
    • Rs4867798 G Enhanced response (CGI-I and ABC hyperactivity subscale)55
    • Rs5326 A Increased response (CGI-I and ABC hyperactivity subscale)55
  • DRD2
    • Rs2283265 T (MPH dose as covariate) Increased risk of an adverse event32
    • A2/A2 stronger response to MPH than A1/A1 and A1/A248
  • DRD3
    • Rs6280 A/A Increased response (CGI-I and ABC hyperactivity subscales)55
    • Rs2134655 Carriers of G for both SNPs Increased treatment failure (CGI-I)32
    • Rs1800828 Carriers of G for both SNPs Increased treatment failure (CGI-I)32
  • DRD4
    • 48-bp VNTR
      • 4R/4R
        • Enhanced Response (ADHD-RS)56
        • Enhanced response (metastudy)38
      • Absence of 4R alleles: lower improvement in hyperactive-impulsive scores (Vanderbilt ADHD Parent and Teacher Rating Scales)47
      • 7R
        • Increased response and gene transfer (TDT)57
        • (combined with L/L genotype of SLC6A4 5HTTLPR): Reduced response (CGAS)53
        • Increased dose required for response (Conners’ Global Index-Parent)58
    • 120-bp promoter duplication
      • L/L: Amplified response (Teacher CLAM-SKAMP)59
      • S/S: Reduced response (CGAS and CGI-S)52
    • Rs11246226 A/A: Increased response (CGI-S and ABC subscale for hyperactivity)55
  • ADRA2A - Adrenoceptor Alpha 2 A Gene
    • Rs1800544 G
      • Reduced inattention (SNAP-IV)6061
      • Increased response (metastudy)38
    • Rs1800544 G/G Increased response (ADHD-RS parent)62
    • Rs1800544 C/C Increased diastolic blood pressure44
14.2.2.4. Neurotransmitter release
  • SNAP25
    • Rs3746544 T/T
      • Improved Response (ADHD-RS)63
      • Reduced response (CGI-S)52
    • Rs3746544 G: Reduced irritability59
    • Rs1051312 C59
      • Decreased motor tics
      • Decreased buccal-lingual movements
      • Reduced picking/biting
14.2.2.5. Neuronal plasticity and synaptic effectors
  • ADGRL3 - Latrophilin 3 (LPHN3) gene
    • Rs6858066 AAG Haplotype: Reduced Response (CGI-I)64
    • Rs1947274 AAG haplotype: reduced response (CGI-I)64
    • Rs6858066 AAG Haplotype: Reduced Response (CGI-I)64
    • Rs6551665 GCA haplotype: enhanced response (CGI-I)64
    • Rs1947274 GCA haplotype: enhanced response (CGI-I)64
    • Rs6858066 GCA haplotype: enhanced response (CGI-I)64
    • Rs6551665 G: Reduced Response (RAST)65
    • Rs1947274 C: Attenuated response (RAST)65
    • Rs6858066 G
      • Increased response (RAST)65
      • Attenuated response (RAST)65
    • Rs6813183 CGC Haplotype
      • Increased response (SNAP-IV)6666
    • Rs1355368 CGC haplotype: increased response (SNAP-IV)66
    • Rs1868790 A/A Reduced response (CGI-S)52
  • BDNF - Brain derived neurotrophic factor - gene (growth factor)
    • Rs6265 G/G Increased response (CGI-S)67
  • NTF3 - Neurotrophin-3 gene
    • Rs6332 A/A
      • Increased emotionality68
      • Increased over-focusing/euphoria68
      • Increased tendency to cry68
      • Increased nail biting68
  • GRM7 - Metabotropic glutamate receptor 7 gene
    • Rs3792452 G/A Enhanced response (ADHD-RS parent, CGI-I)69
  • 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)70
14.2.2.6. Downstream neurotransmitter effects
  • ACT1
    • Intron 3 VNTR: H/H > H/L > L/L: Increased DA release71

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