Abstract
Indinavir, a potent and specific inhibitor of HIV protease, is a known substrate of cytochrome P-450 (CYP) 3A and p-glycoprotein. The purpose of this study is to investigate and compare the inducing effect of dexamethasone (DEX) on CYP3A and p-glycoprotein in the hepatic and intestinal first-pass metabolism of indinavir in rats. Pretreatment of rats with DEX had little effect on the pharmacokinetics (Cl and T1/2) after i.v. administration of indinavir, whereas DEX markedly altered the peak concentration (Cmax) and bioavailability of indinavir after oral dosing. The Cmaxdecreased from 2.8 μM in control rats to 0.28 μM in DEX-treated rats, and bioavailability decreased from 28 to 12.4%. The decreased bioavailability after DEX pretreatment was due mainly to an increase in first-pass metabolism. Intestinal first-pass metabolism (EG) increased from 6% in control rats to 34% in DEX-treated rats, and hepatic first-pass metabolism (EH) increased from 65 to 82%. Analysis of in vitro kinetic data revealed that the increased intestinal and hepatic metabolism by DEX was attributed to an increase in the Vmax, as a result of CYP3A induction, without a significant change in theKm values. DEX pretreatment also induced p-glycoprotein in the intestine and liver of rats. p-Glycoprotein appeared to increase the intestinal metabolism of indinavir whereas it had little effect on the hepatic metabolism of indinavir. Although it has been suggested that the role of intestinal metabolism for some drugs is quantitatively greater than that of hepatic metabolism in the overall first-pass metabolism, the contribution of intestinal metabolism to the overall first-pass metabolism of indinavir in rats is not quantitatively as important as the hepatic metabolism, regardless of DEX induction.
Footnotes
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Send reprint requests to: Jiunn H. Lin, Ph.D., Drug Metabolism, Merck Research Laboratories, WP75A-203, West Point, PA 19486. E-mail: jiunn_lin{at}merck.com
- Abbreviations used are::
- CYP
- cytochrome P-450
- DEX
- dexamethasone
- Cl
- plasma clearance
- EG
- intestinal first-pass metabolism (extraction ratio)
- EH
- hepatic first-pass metabolism (extraction ratio)
- P-gp
- p-glycoprotein
- [AUMC]0-∞
- total area under the first moment of the drug concentration curve from zero to infinity
- F
- bioavailability
- QH
- hepatic blood flow
- QG
- intestinal mucosal blood flow
- Clint,H
- hepatic intrinsic clearance
- Clint,G
- intestinal intrinsic clearance
- fu
- unbound fraction of indinavir in plasma
- 3-MC
- 3-methylcolanthrene
- Received March 16, 1999.
- Accepted June 29, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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