The clearance of racemic bupropion, metabolized selectively by CYP2B6 in vitro, has been used clinically to phenotype CYP2B6 activity, polymorphisms, and drug interactions but has known limitations. Bupropion hydroxylation by CYP2B6 is stereoselective. This investigation assessed the stereoselectivity of bupropion pharmacokinetics and the influence of CYP2B6 induction. Ten healthy volunteers received immediate-release bupropion before and after 7 days of rifampin. Plasma and urine bupropion and hydroxybupropion were analyzed using a stereoselective assay. Plasma area under the curve (AUC(0-infinity)) and maximum concentrations were 3-fold greater for R- than S-bupropion. Bupropion apparent oral clearance was 3- and 2-fold greater for S- than R- and R,S-bupropion, respectively. Hydroxybupropion plasma AUC(0-infinity) and elimination half-life were significantly less for (S,S)- than (R,R)- and the racemate. (S,S)-hydroxybupropion was formation rate limited, whereas (R,R)-hydroxybupropion and the racemate were elimination rate limited. Rifampin doubled both R- and S-bupropion clearance and caused 4-fold increases in both (R,R)- and (S,S)-hydroxybupropion formation clearances. Increases in the plasma hydroxybupropion/bupropion AUC(0-infinity) ratio were greater for (S,S)- than (R,R)-hydroxybupropion. Simplified plasma and urine metrics of stereoselective bupropion metabolism and clearance were identified. Because metabolite formation clearance is the best in vivo metric of enzyme activity and due, therefore, to faster S-bupropion elimination and formation rate-limited (S,S)-hydroxybupropion kinetics, stereoselective S-bupropion hydroxylation and (S,S)-hydroxybupropion formation clearance may be a useful and improved phenotypic probe for CYP2B6.

Ritonavir is the most potent and efficacious inhibitor of cytochrome P4503A (CYP3A), and it is used accordingly for the pharmacoenhancement of other antiretrovirals. Paradoxically, ritonavir induces the clinical metabolism and clearance of many drugs. The mechanism by which ritonavir inhibits and induces clinical drug metabolism is unknown. Ritonavir induces CYP2B6 in human hepatocytes. This investigation tested the hypothesis that ritonavir induces human CYP2B6 in vivo. Thirteen healthy human immunodeficiency virusnegative volunteers underwent a three-way sequential crossover protocol, receiving racemic bupropion after nothing (control), 3 days of treatment with ritonavir, and 2.5 weeks of treatment with ritonavir (400 mg twice a day). Stereoselective bupropion hydroxylation was used as an in vivo probe for CYP2B6 activity. Plasma and urine ( Human immunodeficiency virus (HIV) drugs are notorious perpetrators of drug interactions. The protease inhibitors ritonavir, indinavir, nelfinavir, saquinavir, lopinavir, and amprenavir and the reverse transcriptase inhibitor efavirenz can induce and/or inhibit the metabolism and clearance of numerous drugs (45). Ritonavir is the most potent and efficacious inhibitor of cytochrome P4503A (CYP3A), for which it is both a substrate and a mechanism-based inhibitor (13). Ritonavir is a standard component of highly active retroviral therapy and is included for the pharmacoenhancement of other antiretrovirals (boosting), which is achieved via greater bioavailability and increased and sustained plasma concentrations. Boosting occurs as a result of the inhibition of first-pass and hepatic CYP3A activity and/or the inhibition of P-glycoprotein activity (42).Although traditionally associated with cytochrome P450 (CYP) inhibition, there is growing evidence that protease inhibitors also can cause CYP induction and attendant drug interactions. Specifically, ritonavir has been shown to induce CYP2B6 mRNA, protein expression, and catalytic activity in human hepatocytes in vitro (8,15). Clinically, ritonavir has been shown to increase the metabolism and/or clearance of drugs such as meperidine, ethinyl estradiol, olanzapine, trimethoprim-sulfamethoxazole, and methadone (45). Such induction might be attributable to effects on CYP2B6 activity, since this isoform has been shown to metabolize meperidine (44) and methadone (20,31,47,48). Nevertheless, the clinical effects of ritonavir on human CYP2B6 activity are unknown.The increasing significance of CYP2B6 in human drug metabolism and disposition has been recognized recently, after initially being considered a minor isoform of relative unimportance (12,26,49,54). CYP2B6 catalyzes the bioactivation of the antineoplastic agents ifosphamide, cyclophosphamide, and tamoxifen, the metabolic inactivation of anesthetics and analgesics such as methadone, meperidine, propofol, and ketamine, the biotransformation of abused drugs such as nicotine, ecstasy, and phencyclidine, and pesticides and other environmental contaminants. Notably, CYP2B6 also cataly...