Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients

Aims The objective of the study was to determine the effect of multiple dos es of rifampicin on the steady-state pharmacokinetics of zidovudine and its 5'-glucuronosyl (GZDV) and 3'-amino (AMT) metabolites. Methods Eight asymptomatic HIV-infected patients (seven male, one female) p articipated in this three-period longitudinal study. Each patient received zidovudine (200 mg every 8 h) for 14 days (period 1), followed by rifampici n (600 mg every 24 h) with zidovudine for 14 days (period 2), and then zido vudine alone for a further 14 days (period 3). Blood and urine samples were collected over 6 h on the last day of each period for measurements of zido vudine and GZDV by h.p.l.c.-u.v. and AMT by h.p.l.c.-m.s-m.s. Results Compared with zidovudine-alone values in period 1, 14 days of coadm inistration with rifampicin significantly increased zidovudine oral clearan ce (89%) and formation clearances to GZDV (100%) and AMT (82%). Correspondi ngly, there were decreases in maximum plasma concentration (43%), AUC (47%) and urine recovery (37%) of zidovudine. GZDV/zidovudine and AMT/zidovudine AUC ratios increased by 99% and 36%, respectively, despite a significant 2 9% decrease in AMT AUG. After stopping rifampicin for 14 days, values of th ese pharmacokinetic parameters returned to within 26% of baseline. Over the three periods AMT plasma levels were <18 ng ml(-1) (n=6) and <40 ng ml(-1) (n=2), and molar AMT/zidovudine AUC ratios ranged from 1.7% to 4.5%. Conclusions Rifampicin induced zidovudine glucuronidation and amination pat hways resulting in decreased plasma and urine exposures to zidovudine. AMT plasma exposure decreased because induction was more pronounced for the maj or GZDV metabolite. The magnitude of the residual inductive effect was mini mal at 14 days after stopping rifampicin.