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.

Figure 1

Time course of plasma concentrations of A) buprenorphine (Bup), B) norbuprenorphine (Nor), C) buprenorphine-3-glucuronide (B3G) and D) norbuprenorphine-3-glucuronide (N3G) for male (❍) and female (■) subjects who were on maintenance dosing with 16/4 mg buprenorphine/naloxone, and had negative cocaine urine tests just prior to the pharmacokinetic session. Values are the mean ± SEM for 20 males and 11 females. Values were from the initial pharmacokinetic session for subjects who participated in more than one study.