Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone‐ and buprenorphine‐maintained subjects

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Although not well recognized, methadone inhibits CYP2D6 in vivo and in vitro and UGT2B7 and 2B4 in vitro.• We aimed to investigate the effect of methadone on the pathways of codeine metabolism, namely O-demethylation (CYP2D6), 6-glucuronidation (UGT2B4/7) and N-demethylation (CYP3A4/2C8), in subjects maintained on methadone or buprenorphine as a control. WHAT THIS STUDY ADDS• Compared with subjects on buprenorphine, methadone reduced the clearance of codeine to morphine and to codeine-6-glucuronide but had no effect on norcodeine formation.• Plasma morphine concentrations remained unchanged, as although its formation was reduced, its metabolism to M3G and M6G was also reduced.• Metabolic drug interactions with methadone cannot assume substrate-dependent inhibition. AIMSTo compare the O-demethylation (CYP2D6-mediated), N-demethylation (CYP3A4-mediated) and 6-glucuronidation (UGT2B4/7-mediated) metabolism of codeine between methadone-and buprenorphine-maintained CYP2D6 extensive metabolizer subjects. METHODSTen methadone-and eight buprenorphine-maintained subjects received a single 60 mg dose of codeine phosphate. Blood was collected at 3 h and urine over 6 h and assayed for codeine, norcodeine, morphine, morphine-3-and -6-glucuronides and codeine-6-glucuronide. RESULTSThe urinary metabolic ratio for O-demethylation was significantly higher (P = 0.0044) in the subjects taking methadone (mean Ϯ SD, 2.8 Ϯ 3.1) compared with those taking buprenorphine (0.60 Ϯ 0.43), likewise for 6-glucuronide formation (0.31 Ϯ 0.24 vs. 0.053 Ϯ 0.027; P < 0.0002), but there was no significant difference (P = 0.36) in N-demethylation. Similar changes in plasma metabolic ratios were also found. In plasma, compared with those maintained on buprenorphine, the methadone-maintained subjects had increased codeine and norcodeine concentrations (P < 0.004), similar morphine (P = 0.72) and lower morphine-3-and -6-and codeine-6-glucuronide concentrations (P < 0.008). CONCLUSIONMethadone is associated with inhibition of CYP2D6 and UGTs 2B4 and 2B7 reactions in vivo, even though it is not a substrate for these enzymes. Plasma morphine was not altered, owing to the opposing effects of inhibition of both formation and elimination; however, morphine-6-glucuronide (analgesically active) concentrations were substantially reduced. Drug interactions with methadone are likely to include drugs metabolized by various UGTs and CYP2D6.

A review of pharmacological interactions between HIV or hepatitis C virus medications and opioid agonist therapy: implications and management for clinical practice

“…Inactive metabolites and some unmetabolized methadone are excreted in the bile and urine [64]. Although not normally thought of as an inhibitor, a recent in vivo study suggests that methadone is associated with inhibition of CYP 2D6 and UDP-glucuronosyl transferase (UGT) 2B4 and 2B7 [65]. The clinical significance of this inhibition is currently unknown.…”

Inhibition of CYP2D6‐mediated tramadol O‐demethylation in methadone but not buprenorphine maintenance patients

“…Nonetheless, this study further indicates that tramadol can be used safely in BMT patients for the treatment of acute and chronic pain. Our observations in MMT patients adds to our previous report that codeine is also unlikely to be an effective analgesic in MMT due to reduced CYP2D6‐mediated O‐demethylation of codeine to morphine and its glucuronides [22]. Therefore, it can be postulated that any opioid requiring O‐demethylation via CYP2D6 to produce an active metabolite will not provide adequate analgesia in MMT patients, so alternative analgesics that do not rely on CYP2D6 mediated metabolism need future consideration in this population.…”

“…With regard to tramadol use in opioid maintenance patients, there is potential for methadone to inhibit the formation of M1 due to its competitive inhibition of the CYP2D6-mediated O-demethylation of dextromethorphan [20,21]. This is supported by our recent study that demonstrated that methadone significantly inhibited the CYP2D6-mediated O-demethylation of codeine to morphine and its glucuronides [22]. Clinically, this has the potential to alter tramadol analgesia in a similar manner as paroxetine (a potent CYP2D6 inhibitor) that reversed tramadol analgesia to cold pressor pain [23].…”

Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response

“…This effect seems to be related to induction of CYP2B6 and CYP3A4 mRNA expression (Campbell et al, 2013) and may explain the requests for higher doses by some drug addicts (Horns et al, 1975). Moreover, another in vivo study demonstrated that methadone is associated with inhibition of CYP2D6 and UDP-glucuronosyl transferase (UGT) 2B4 and 2B7 (Gelston et al, 2012). The inhibitory effect on UGT2B7 is shown to have an important role in opiate withdrawal symptoms, including pupil size and tremor (Tian et al, 2012).…”