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PubMed2004

Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone.

BACKGROUND: The disposition of the long-acting opioid methadone, used to prevent opiate withdrawal and treat short- and long-lasting pain, is highly variable. Methadone undergoes N -demethylation to the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP), catalyzed in vitro by intestinal, hepatic, and expressed cytochrome P450 (CYP) 3A4. However, the role of CYP3A4 in human methadone disposition in vivo is unclear. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) methadone metabolism and clearance in humans. METHODS: Healthy volunteers were studied in a randomized, balanced, 4-way crossover study. They received intravenous (IV) midazolam (to assess CYP3A4 activity) and then simultaneous oral deuterium-labeled and IV unlabeled methadone after pretreatment with rifampin (INN, rifampicin) (hepatic/intestinal CYP3A induction), troleandomycin (hepatic/intestinal CYP3A inhibition), grapefruit juice (selective intestinal CYP3A inhibition), or nothing. Methadone effects were measured by dark-adapted pupil diameter. CYP isoforms catalyzing methadone metabolism by human liver microsomes and expressed CYPs in vitro were also evaluated. RESULTS: Methadone had high oral bioavailability (70%) and low intestinal (22%) and hepatic (9%) extraction, and there was a significant correlation ( r = 0.94, P <.001) between oral bioavailability and intestinal (but not hepatic) availability. Rifampin decreased bioavailability and oral and IV methadone plasma concentrations and increased IV clearance (4.42 +/- 1.00 mL. kg -1. min -1 versus 1.61 +/- 0.67 mL. kg -1. min -1, P <.05) and oral clearance (8.50 +/- 3.68 mL. kg -1. min -1 versus 2.05 +/- 0.92 mL. kg -1. min -1, P <.05), EDDP/methadone area under the curve (AUC) ratios, EDDP formation clearances, and hepatic extraction (0.27 +/- 0.06 versus 0.09 +/- 0.04, P <.05). Troleandomycin and grapefruit juice decreased the EDDP/methadone AUC ratio after oral methadone (0.17 +/- 0.10 and 0.14 +/- 0.06 versus 0.27 +/- 0.20, P <.05) but not IV methadone and had no effect on methadone plasma concentrations, IV clearance (1.29 +/- 0.41 mL. kg -1. min -1 and 1.48 +/- 0.55 mL. kg -1. min -1 ) or oral clearance (2.05 +/- 1.52 mL. kg -1. min -1 and 1.89 +/- 1.07 mL. kg -1. min -1 ), or other kinetic parameters. There was no correlation between methadone clearance and hepatic CYP3A4 activity. Pupil diameter changes reflected plasma methadone concentrations. In vitro experiments showed a predominant role for both CYP3A4 and CYP2B6 in liver microsomal methadone N -demethylation. CONCLUSION: First-pass intestinal metabolism is a determinant of methadone bioavailability. Intestinal and hepatic CYP3A activity only slightly affects human methadone N -demethylation but has no significant effect on methadone concentrations, clearance, or clinical effects. Greater rifampin effects, compared with troleandomycin and grapefruit juice, on methadone disposition suggest a major role for intestinal transporters and for other CYPs, such as CYP2B6. Interindividual variability and drug interactions affecting intestinal transporter and hepatic CYP3A and CYP2B6 activity may alter methadone disposition.

Adult↗
PubMed1996

An investigation of medical examiner cases in which methadone was detected, Harris County, Texas, 1987-1992.

In 1991, media reports of an increase in the number of deaths attributed to methadone toxicity in Harris County, Texas, raised public concern about the safety of methadone. This concern was heightened by publicity surrounding the closure of three Harris County methadone maintenance treatment programs due to their poor compliance with federal methadone regulations. In response to this concern, the Texas Department of Public Health requested that the Centers for Disease Control and Prevention (CDC) assist in an epidemiologic study to determine the extent of methadone-related mortality in Harris County during 1991 and to determine the role of methadone maintenance treatment in these deaths. We reviewed cases investigated by the Harris County Medical Examiner's Office from 1987 through 1992 in which methadone was detected by postmortem drug testing. The autopsy reports for cases occurring in 1991 were also reviewed by three independent forensic pathologists who were asked to determine the role of methadone in the death. In addition, we attempted to document Harris County methadone maintenance treatment program enrollment for each decedent. We identified 91 decedents in whom methadone was detected at the time of death, with the largest number of cases occurring in 1991 (n = 27). Other substances, including alcohol, were detected in 85% of the cases. The Harris County Medical Examiner attributed 11 of the deaths to methadone toxicity. No more than three cases per year from 1987 through 1992 were attributed to methadone toxicity. In contrast, 34 deaths were attributed to polydrug toxicity, the largest number occurring in 1991 (n = 11). There was good agreement between the results of the independent review and the opinions of the Harris County Medical Examiner. Only 20% of the decedents were found to have been enrolled in a Harris County methadone maintenance treatment program at the time of death. Four people died of drug toxicity shortly after enrolling in a methadone maintenance treatment program. We found an increase in the number deaths occurring in Harris County, Texas, in 1991 in which methadone was detected. We also found that methadone blood levels were higher among decedents identified for 1991 and 1992 than among those identified in the previous years studied. However, we did not find evidence that the cause of these deaths could be attributed solely to methadone toxicity. Instead, for all years studied, the use of multiple drugs was the leading cause of death among people in whom methadone was detected. This finding points out the difficulties involved in determining the role of methadone as a cause of death.

Adult↗