Back to Search
Start Over
Induction of P-glycoprotein and cytochrome P450 3A by HIV protease inhibitors.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2001 May; Vol. 29 (5), pp. 754-60. - Publication Year :
- 2001
-
Abstract
- P-Glycoprotein (Pgp) and cytochrome P450 3A (CYP3A) are important enzymes affecting the disposition of HIV protease inhibitors (HIV PIs). After multiple dosing experiments in rats, decreases in the plasma concentrations and area under plasma concentration-time curve (AUC) for HIV PIs have been observed. The purpose of these studies was to determine the changes in Pgp and CYP3A expression and HIV PI plasma exposure after multiple doses of HIV PIs. Male rats were orally dosed with an amprenavir prodrug (450 mg/kg/day amprenavir-equivalent) or nelfinavir (175 mg/kg/day) for 1 or 14 days. Relative to day 1, the C(max) and the AUC for amprenavir at day 14 were decreased by 33 and 51%, respectively. Similarly, the plasma concentration of nelfinavir at 1 h after the last dose (C(max)) was reduced by 52% after multiple doses. Compared with controls, dosing of amprenavir for 14 days increased intestinal Pgp and hepatic CYP3A protein levels by 59 and 151%, respectively, but did not alter intestinal CYP3A protein levels. In contrast, amprenavir treatment did not result in an increase in hepatic CYP3A activity. Nelfinavir treatment increased expression of intestinal Pgp and hepatic CYP3A levels by 83 and 85%, respectively, but not hepatic Pgp or intestinal CYP3A. HIV PIs also induced Pgp expression in the LS174T human intestinal cell line. These results indicate that HIV protease inhibitors induce both intestinal Pgp and hepatic CYP3A and suggest that induction of Pgp and CYP3A is a possible mechanism reducing drug exposure after multiple doses.
- Subjects :
- Animals
Anti-HIV Agents blood
Carbamates
Cytochrome P-450 CYP3A
Furans
HIV Protease Inhibitors blood
Humans
Intestinal Mucosa metabolism
Intestines drug effects
Intestines enzymology
Liver drug effects
Liver enzymology
Liver metabolism
Male
Nelfinavir blood
Nelfinavir pharmacology
Rats
Rats, Wistar
Sulfonamides blood
Sulfonamides pharmacology
Tumor Cells, Cultured
ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis
Anti-HIV Agents pharmacology
Aryl Hydrocarbon Hydroxylases
Cytochrome P-450 Enzyme System biosynthesis
HIV Protease Inhibitors pharmacology
Oxidoreductases, N-Demethylating biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0090-9556
- Volume :
- 29
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 11302944