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Role of small intestinal cytochromes p450 in the bioavailability of oral nifedipine.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2007 Sep; Vol. 35 (9), pp. 1617-23. Date of Electronic Publication: 2007 Jun 13. - Publication Year :
- 2007
-
Abstract
- To determine the effect of intestinal cytochrome P450 (P450) enzymes on the bioavailability of oral drugs, we have examined the metabolism of nifedipine, an antihypertensive drug and a model substrate of CYP3A4, in mouse models having deficient expression of the NADPH-cytochrome P450 reductase. Initial studies were performed on Cpr-low (CL) mice, which have substantial decreases in Cpr expression in all tissues examined, including the small intestine. In CL mice, area under the concentration-time curve (AUC) values for blood nifedipine after intraperitoneal and oral dosing were 1.8- and 4.0-fold, respectively, higher than in wild-type mice, despite increased expression of multiple P450 enzymes in both liver and intestine. The greater extent of the increase in the AUC value for oral than for intraperitoneal nifedipine suggested that intestinal P450s influence the bioavailability of oral nifedipine, a notion supported by results from further studies on LCN and CL-LCN mice. The LCN mice, which have liver-specific Cpr deletion, had 6.9-fold higher AUC values and 2.2-fold higher C(max) values for blood nifedipine than did wild-type mice after oral nifedipine, consistent with the critical role of hepatic P450s in systemic nifedipine clearance. However, in the CL-LCN mice, which have global decreases in Cpr expression in all tissues examined and Cpr deletion in the liver, AUC and C(max) values for oral nifedipine were, respectively, 2.2- and 1.8-fold higher than in LCN mice, confirming the fact that P450-catalyzed metabolism in the small intestine, the portal-of-entry organ for oral drugs, plays an important role in the first-pass clearance of oral nifedipine.
- Subjects :
- Animals
Area Under Curve
Biological Availability
Blotting, Western
Calcium Channel Blockers administration & dosage
Chromatography, High Pressure Liquid
Female
Half-Life
Male
Mice
Mice, Inbred C57BL
Microsomes drug effects
Microsomes metabolism
NADPH-Ferrihemoprotein Reductase genetics
NADPH-Ferrihemoprotein Reductase metabolism
Nifedipine administration & dosage
Calcium Channel Blockers pharmacokinetics
Cytochrome P-450 Enzyme System metabolism
Intestine, Small enzymology
Nifedipine pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0090-9556
- Volume :
- 35
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 17567730
- Full Text :
- https://doi.org/10.1124/dmd.107.016543