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- W2077774886 abstract "Digoxin, a cardiac glycoside, is a substrate of the multidrug transporter P-glycoprotein (Pgp), and in rats has also been identified as a substrate for cytochrome P450 3A (CYP3A). Ketoconazole, an antifungal agent, 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 effects of ketoconazole on digoxin absorption and disposition in rats. Digoxin was administered intravenously or orally with or without a concomitant oral dose of ketoconazole. When given intravenously, digoxin AUC increased from 93 +/- 22 to 486 +/- 26 microg x h/l with ketoconazole administration. Similarly, ketoconazole raised the AUC of orally administered digoxin from 63 +/- 17 to 411 +/- 50 microg x h/l. Concomitant ketoconazole administration prolonged digoxin elimination, yielding a nonlinear pharmacokinetic profile. Using time-averaged values, digoxin bioavailability increased from 0.68 +/- 0.18 to 0.84 +/- 0.10, while mean absorption time was reduced from 1.1 +/- 0.4 to 0.3 +/- 0.1 h. Thus, in rats, ketoconazole increases digoxin plasma concentrations, rate of absorption and bioavailability. Although the effects of ketoconazole on AUC could be explained by inhibition of both CYP3A and Pgp, which cannot be differentiated in this study, the decreased mean absorption time can only be explained by inhibition of Pgp in the intestine." @default.
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- W2077774886 date "1998-01-01" @default.
- W2077774886 modified "2023-10-14" @default.
- W2077774886 title "Effects of Ketoconazole on Digoxin Absorption and Disposition in Rat" @default.
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- W2077774886 doi "https://doi.org/10.1159/000028214" @default.
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