Effect of dexamethasone on the intestinal first-pass metabolism of indinavir in rats: Evidence of cytochrome P-450 A and P-glycoprotein induction

Indinavir, a potent and specific inhibitor of HIV protease, is a known subs trate of cytochrome P-450 (CYP) 3A and p-glycoprotein. The purpose of this study is to investigate and compare the inducing effect of dexamethasone (D EX) on CYP3A and p-glycoprotein in the hepatic and intestinal first-pass me tabolism of indinavir in rats. Pretreatment of rats with DEX had little eff ect on the pharmacokinetics (Cl and T-1/2) after i.v. administration of ind inavir, whereas DEX markedly altered the peak concentration (C-max) and bio availability of indinavir after oral dosing. The C-max decreased from 2.8 m u M in control rats to 0.28 mu M in DEX-treated rats, and bioavailability d ecreased from 28 to 12.4%. The decreased bioavailability after DEX pretreat ment was due mainly to an increase in first-pass metabolism. Intestinal fir st-pass metabolism (EG) increased from 6% in control rats to 34% in DEX-tre ated rats, and hepatic first-pass metabolism (EH) increased from 65 to 82%. Analysis of in vitro kinetic data revealed that the increased intestinal a nd hepatic metabolism by DEX was attributed to an increase in the V-max, as a result of CYP3A induction, without a significant change in the K-m value s. DEX pretreatment also induced p-glycoprotein in the intestine and liver of rats. p-Glycoprotein appeared to increase the intestinal metabolism of i ndinavir whereas it had little effect on the hepatic metabolism of indinavi r. Although it has been suggested that the role of intestinal metabolism fo r some drugs is quantitatively greater than that of hepatic metabolism in t he overall first-pass metabolism, the contribution of intestinal metabolism to the overall first-pass metabolism of indinavir in rats is not quantitat ively as important as the hepatic metabolism, regardless of DEX induction.