EFFECTS OF KETOCONAZOLE ON DIGOXIN ABSORPTION AND DISPOSITION IN RAT

Digoxin, a cardiac glycoside, is a substrate of the multidrug transpor ter P-glycoprotein (Pgp), and in rats has also been identified as a su bstrate for cytochrome P-450 3A (CYP3A). Ketoconazole, an antifungal a gent, was shown to inhibit Pgp in a multidrug-resistant cell line, and is known to be a potent inhibitor of CYP3A. Here, we determined the e ffects of ketoconazole on digoxin absorption and disposition in rats. Digoxin was administered intravenously or orally with or without a con comitant oral dose of ketoconazole. When given intravenously, digoxin AUC increased from 93 +/- 22 to 486 +/- 26 mu g.h/I with ketoconazole administration. Similarly, ketoconazole raised the AUC of orally admin istered digoxin from 63 +/- 17 to 411 +/- 50 pg hm. Concomitant ketoco nazole administration prolonged digoxin elimination, yielding a nonlin ear pharmacokinetic profile. Using time-averaged values, digoxin bioav ailability increased from 0.68 +/- 0.18 to 0.84 +/- 0.10, while mean a bsorption time was reduced from 1.1 +/- 0.4 to 0.3 +/- 0.1 h. Thus, in rats, ketoconazole increases digoxin plasma concentrations, rate of a bsorption and bioavailability. Although the effects of ketoconazole on AUC could be explained by inhibition of both CYP3A and Pgp, which can not be differentiated in this study, the decreased mean absorption tim e can only be explained by inhibition of Pgp in the intestine.