Received 28 March 2000 Copyright # 2001 John Wiley & Sons, Ltd. Accepted 11 August 2001 BIOPHARMACEUTICS & DRUG DISPOSITION Biopharm. Drug Dispos. 22: 157–168 (2001) DOI: 10.1002/bdd.268 CYP3A Inductive Potential of the Rifamycins, Rifabutin and Rifampin, in the Rabbit Allan Weber a,b,y , Mindy Kaplan b , Shazia A. Chughtai b , Leah A. Cohn b , Arnold L. Smith b and Jashvant D. Unadkat a, * a Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA b Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA ABSTRACT: Rifabutin is effective in the treatment and prevention of Mycobacterium avium infection in people with HIV infection. Rifabutin is structurally related to another rifamycin, rifampin, a well- known inducer of the human P-450 isoform 3A. The rabbit isoform CYP3A6 and the human isoform CYP3A4 have similar P-450 predominance and substrate specificity and are both induced by rifampin. Our goal was to predict the CYP3A induction capacity of rifabutin and to determine if ex vivo CYP3A induction potential of rifamycins is predictive of that obtained in vivo. We determined the in vivo and ex vivo CYP3A6 induction by 4 days of treatment with rifabutin (100 mg/kg), rifampin (100 mg/kg), or vehicle (DMSO) in the rabbit. The ex vivo measures were CYP3A6 activity (N-demethylation of erythromycin and hydroxylation of triazolam) and CYP3A content in rabbit hepatic microsomes preparations. The in vivo measures were oral clearance of triazolam and its formation clearance to its hydroxylated metabolites, a-hydroxytriazolam and 4-hydroxytriazolam. Rifampin increased CYP3A6 activity by 2- to 3-fold in hepatic microsomes compared to vehicle. Rifabutin increased CYP3A content 1.7-fold, but did not significantly increase microsomal CYP3A6 activity. Oral triazolam clearance and formation clearances to the two hydroxylated metabolites were 2- to 3-fold greater in rabbits treated with rifampin. These clearances were unaffected by rifabutin administration. Ex vivo enzyme activities correlated with in vivo changes in clearance of triazolam and the formation clearance to its hydroxylated metabolites. Rifabutin is a weaker inducer of CYP3A6 than rifampin. These data suggest that ex vivo enzyme activity is a viable approach to predict in vivo inductive potential of CYP3A inducers. Copyright # 2001 John Wiley & Sons, Ltd. Key words: rifampin; rifabutin; CYP3A; rabbit; induction; triazolam Introduction Rifabutin is effective in treatment and prophy- laxis of M. avium [1,2] and M. tuberculosis [3] infection. Rifabutin is structurally related to rifampin, a firstline antibiotic against tuberculo- sis and a well-known inducer of CYP3A and CYP2C in humans. Because rifabutin is routinely administered to people with AIDS who simulta- neously receive other CYP3A substrates (e.g. macrolide antibiotics, antifungal agents, and protease inhibitors), the potential of clinically relevant drug interactions between these drugs is significant. To predict these interactions, the potential of rifabutin, relative to that of rifampin, to induce CYP3A must be known. Therefore, our goals were to compare, in the rabbit, the relative CYP3A inductive potential of rifabutin and * Corresponding author. Department of Pharmaceutics, Univer- sity of Washington, Box 357610 H272 Health Sciences Building, Seattle, WA 98195, USA. E-mail: jash@u.washington.edu y Present address: Allergan, 2525 Dupont Dr., Irvine, CA, USA.