Gender differences in pharmacokinetics of maintenance dosed buprenorphine

Abstract

Aims Gender differences are known to occur in the pharmacokinetics of many drugs. Mechanisms may include differences in body composition, body weight, cardiac output, hormonal status, and use of different co-medications. Recently subtle gender-dependent differences in cytochrome P450 (CYP) 3A-dependent metabolism have been demonstrated. Buprenorphine N-dealkylation to norbuprenorphine is primarily performed by CYP3A. We therefore asked whether gender-dependent differences occur in the pharmacokinetics of buprenorphine. Methods A retrospective examination was made of control (buprenorphine/naloxone-only) sessions from a number of drug interaction studies between buprenorphine and antiretroviral drugs. Twenty males and eleven females were identified who had a negative cocaine urine test prior to participation in the control session and were all on the same maintenance dose (16/4 mg) of sublingual buprenorphine/naloxone. Pharmacokinetic data from their control sessions (buprenorphine/naloxone only) were sorted by gender and compared using the two-sample t-test. Results Females had significantly higher area under the plasma concentration curve (AUC) and maximum plasma concentrations for buprenorphine, norbuprenorphine and norbuprenorphine-3-glucuronide. AUCs relative to dose per body weight and surface area were significantly higher for only norbuprenorphine. AUCs relative to lean body mass were, however, not significantly different. Conclusions Gender-related differences exist in the pharmacokinetics of buprenorphine; differences in body composition appear to have a major impact; differences in CYPA-dependent metabolism may also contribute.

Transdermal buprenorphine—interesting observations on the metabolite norbuprenorphine levels in elderly subjects

“…Interestingly, corroborative evidence has been reported in a recent study, where buprenorphine has been shown to inhibit the glucuronidation of norbuprenorphine, the only clearance pathway for norbuprenorphine, in multiple in vitro systems [8]. The results of this recent study assumes greater importance since 3-norbuprenorphine glucuronide was found to be a major circulatory species with five-to 13-fold higher levels as compared to 3-buprenorphine glucuronide in several clinical studies following buprenorphine dosing [9,10].…”

“…Interestingly, although the formation of nurbuprenorphine suggests a clear route dependency, as evidenced by the norbuprenorphine/buprenorphine exposure ratios following transdermal (average 0.32), sublingual (average 1.52) and intravenous (average 0.19) drug administration of buprenorphine [4,9,11], the involvement of the glucuronidation pathway for the clearance of norbuprenorphine is highly inevitable regardless of the route of administration. Hence, the qualitative evidence gathered by the cursory data analysis in this report needs further probing because increased circulatory levels of norbuprenorphine in the elderly may contribute to several safety issues, including respiratory depression.…”

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

“…The metabolic ratios of 7-hydroxyl-veratramine and veratramine-3-O-sulfate calculated in plasma were 27.8 ± 4.8% and 33.7 ± 16.7%, respectively, in male rats compared with 3.4 ± 1.2% and 93.8 ± 1.8% in female rats, which indicated distinct gender differences. Mechanisms of gender-dependent pharmacokinetics may include differences in cardiac output, body composition, body weight, hormonal status, and metabolism between genders (57,58). One factor commonly known to contribute to gender-related metabolism, the major reason for gender difference on pharmacokinetic behavior, is the differential expression of drug-processing enzymes including phase I and phase II metabolic enzymes (P450s, sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases) (59).…”

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

“…Women, for example, have a higher AUC of buprenorphine than men, possibly due to differences in body composition, as well as potential differences in CYP 3A4 [27]. …”