Received for publication June 5, 2006.
Revised August 9, 2006.
Accepted for publication August 9, 2006.

Elucidating the Effect of Final Day Dosing of Rifampin in Induction Studies on Hepatic Drug Disposition and Metabolism

Abstract

Because rifampin (RIF) induces hepatic enzymes and inhibits uptake transporters, dosing a drug that is a dual substrate of enzymes and uptake transporters on the final day of an inducing regimen should exhibit less inductive effect than dosing on the following day in the absence of RIF since RIF decreases drug uptake into liver. In vitro and in vivo rat studies were conducted using digoxin as a model substrate. Digoxin was administered to an uninduced control group to obtain baseline values. The second group (induced with dexamethasone) received digoxin alone mimicking administration of a test drug one day following completion of an induction regimen, whereas the third group (induced) received digoxin with RIF mimicking the concomitant dosing on the final day of an induction regimen. Results from hepatocyte concentration-time course studies showed that compared to uninduced control (26.9±1.3 µM•min/mg), digoxin AUC in induced cells when no RIF is present decreased significantly (13.7±0.9 µM•min/mg, p<0.01) suggesting induction of cyp3a. However, digoxin AUC for induced cells in the presence of RIF (27.3±0.9 µM•min/mg) matched the control. Rat pharmacokinetic studies showed that compared to digoxin clearance in uninduced controls (7.08±1.57 ml/min/kg), digoxin clearance in induced rats increased two-fold (15.6±3.7 ml/min/kg, p<0.001), but when RIF was co-administered in the induced rats, digoxin clearance (7.14±1.24 ml/min/kg) overlapped with control. That is, concomitant dosing of RIF and digoxin masked the inductive effect. To observe full inductive effects, test drugs should be administered one day after final dosing of RIF to minimize potential OATP inhibition effects.

Key words: OATP/Oatp, digoxin, enzyme induction, rifampin, transporter inhibition, transporter/enzyme interplay

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