MPH Part 5: Metabolism
5.1. Degradation of MPH by CES1
Methylphenidate (MPH) is broken down to ritalinic acid via CES1.
A comprehensive description can be found at CES1 metabolizing enzyme
5.2. Influence of CYP2D6 on the effect of MPH and ATX
In principle, CYP enzymes are not involved in the degradation of MPH.123 One study found no correlation between different metabolization gene variants of CYP2D6 or CYP2C19 (only an increased rate of CYP2C19 ultra-metabolizers among people with ADHD).4
There is therefore only a relatively low risk of drug interactions with MPH.5
Although MPH is degraded by CES1 and not by CYP2D6, different CYP gene variants showed significant influence on MPH efficacy:6
An improvement in ADHD symptoms following MPH administration was found in the 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
A double-blind study in n = 199 adolescents with ADHD with stepwise titration for dose optimization, the CYP2D6 gene variant influenced not only the effect of atomoxetine, which is known to be degraded via CYP2D6, but also the effect of MPH.7 However, the differences were not resounding and mainly concerned the speed of dose adjustment.
- CYP2D6 normal metabolizers responded well to MPH such as ATX.
- DAT1 9/10 showed a faster dose-response relationship to ATX than DAT1 10/10
- DAT1 9/9 genotypes did not respond to ATX with increasing dose (stronger?)
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. ↥
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. ↥
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. ↥
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. ↥
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. ↥
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. ↥
Bishop JR, Zhou C, Gaedigk A, Krone B, Kittles R, Cook EH, Newcorn JH, Stein MA (2024): Dopamine Transporter and CYP2D6 Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study. J Child Adolesc Psychopharmacol. 2024 Dec;34(10):458-469. doi: 10.1089/cap.2024.0069. PMID: 39387268; PMCID: PMC11807865. ↥