In vitro assessment of 24 CYP2D6 allelic isoforms on the metabolism of methadone

Abstract

CYP2D6 is an important member of the cytochrome P450 (CYP450) enzyme super family, with at least 100 CYP2D6 alleles being previously identified. Genetic polymorphisms of CYP2D6 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The aim of this study was to clarify the catalytic activities of 24 CYP2D6 alleles on the oxidative in vitro metabolism of methadone. Reactions were incubated with 50-2000 µM methadone for 30 min at 37 °C and terminated by cooling to -80 °C immediately. Methadone and the major metabolite EDDP were analyzed by an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) system. Compared with wild-type CYP2D6*1, most variants showed significantly altered values in V and intrinsic clearance (V /K ). Only three variants (CYP2D6*88, *91 and E215K) exhibited markedly increased intrinsic clearance values, and one variant CYP2D6*94 showed no significant difference. On the other hand, the kinetic parameters of two CYP2D6 variants (CYP2D6*92 and *96) could not be determined because they had no detectable enzyme activity, whereas 18 variants exhibited significantly decreased values. To sum up, this study demonstrated that more attention should be paid in clinical administration of methadone to individuals carrying these CYP2D6 alleles. Copyright © 2016 John Wiley & Sons, Ltd.

Functional characterization of CYP2C19 variants in nebivolol 4‐hydroxlation in vitro

“…[11][12][13] However, our previous study showed that CYP2C19 and CYP3A4 can contribute, to some extent, to this pathway for the metabolism of nebivolol 4-hydroxylation. 11 It seems that several CYP450 enzymes may be involved in nebivolol metabolism as well as some drugs, such as fluoxetine, 14,15 methadone, 16,17 and citalopram. 18,19 Most importantly, CYP2C19 polymorphisms are deeply Table S1 in the Supporting Information.…”

Inhibitory effect of isavuconazole, ketoconazole, and voriconazole on the pharmacokinetics of methadone in vivo and in vitro

“…Data from in vitro studies suggested that CYP3A4, CYP2D6, CYP2C8, CYP2C9, and CYP2C19 play a role in the metabolism of methadone to its active metabolite, 2‐Ethyl‐1,5‐dimethyl‐3,3‐diphenylpyrrolinium (EDDP) . Methadone is primarily metabolized by CYP3A4, and to a lesser extent by CYP2C8, CYP2C9, CYP2C19, and CYP2D6 . Since methadone is a substrate of CYP enzymes, the changes of CYP activities may influence the pharmacokinetic profile of methadone, involving the concentration, clearance and bioavailability of methadone.…”

Silibinin affects the pharmacokinetics of methadone in rats

“…Methadone maintenance treatment (MMT) is widely used to reduce the harms of opioid use disorder . Methadone is primarily metabolized via N‐demethylation to an inactive metabolite, 2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidene (EDDP) . In vitro metabolic investigations, using human liver microsomes or recombinant cytochrome P450 enzymes, suggested that CYP2D6, 3A4, and 2C19 played an important role in the metabolism of methadone .…”

“…2 Methadone is primarily metabolized via N-demethylation to an inactive metabolite, 2-ethylidene-1,5dimethyl-3,3-diphenylpyrrolidene (EDDP). 3 In vitro metabolic investigations, using human liver microsomes or recombinant cytochrome P450 enzymes, suggested that CYP2D6, 3A4, and 2C19 played an important role in the metabolism of methadone. [3][4][5] In vivo investigations also suggested that CYP3A4 and CYP2C19 genetic polymorphism, influencing methadone dose and tolerance, contributed to the methadone poor metabolizer phenotype.…”

“…3 In vitro metabolic investigations, using human liver microsomes or recombinant cytochrome P450 enzymes, suggested that CYP2D6, 3A4, and 2C19 played an important role in the metabolism of methadone. [3][4][5] In vivo investigations also suggested that CYP3A4 and CYP2C19 genetic polymorphism, influencing methadone dose and tolerance, contributed to the methadone poor metabolizer phenotype. 6,7 Drug addicts are known to be at high risk of infection of viral hepatitis A, B, and C (HAV, HBV, and HCV).…”