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 1 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 with uninduced control (26.9 ± 1.3 μM · min/mg), digoxin area under the time-concentration curve (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 with digoxin clearance in uninduced controls (7.08 ± 1.57 ml/min/kg), digoxin clearance in induced rats increased 2-fold (15.6 ± 3.7 ml/min/kg; p < 0.001), but when RIF was coadministered 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 1 day after final dosing of RIF to minimize potential organic anion transporting polypeptide inhibition effects.
Footnotes
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This study was funded in part by National Institutes of Health Grants GM61390 and HD40543 and by an unrestricted grant from Amgen Inc. L.Z.B. serves as a consultant to Amgen.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.108282.
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ABBREVIATIONS: RIF, rifampin; PXR, pregnane X receptor; OATP/Oatp, organic anion transporting polypeptide; Dg3, digoxin; AUC, area under the concentration-time curve; P-gp, P-glycoprotein; DEX, dexamethasone; Dg0, aglycone digoxigenin; HPLC, high-performance liquid chromatography; Dg2, digoxigenin bis-digitoxoside; Dg1, digoxigenin monodigitoxoside; PK, pharmacokinetics; ACN, acetonitrile; LC-MS, liquid chromatography-mass spectrometry; HEK, human embryonic kidney; CL, clearance; Vss, volume of distribution at steady state.
- Received May 24, 2006.
- Accepted August 9, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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