Extrahepatic first-pass metabolism of nifedipine in the rat

Biopharm Drug Dispos. 1997 Aug;18(6):509-22. doi: 10.1002/(sici)1099-081x(199708)18:6<509::aid-bdd38>3.0.co;2-5.

Abstract

The peroral (p.o.) bioavailability of nifedipine is reported to range from about 45 to 58% in the rat; this compares favourably to human beings. The metabolism of nifedipine is similar in rats and humans (oxidation of the dihydropyridine ring), with the liver believed to be solely responsible for the systemic clearance of the drug and the observed first-pass effect after p.o. dosing. The purpose of this study was to determine whether intestinal metabolism also contributes to the first-pass elimination of nifedipine in the rat. The systemic availabilities of nifedipine doses given by po, intracolonic (i.c.), and intraperitoneal (i.p.) routes of administration were compared to that for an intravenous (i.v.) dose (in each case a dose of 6 mg kg-1 was given) using adult male Sprague-Dawley rats (249-311 g, n = 6 or 7/group). The geometric mean of systemic nifedipine plasma clearance after i.v. dosing was 10.3 mL min-1 kg-1. The nifedipine blood-to-plasma ratio was found to be about 0.59. Therefore, the systemic blood clearance of nifedipine was about 17.5 mL min-1 kg-1; which, compared to the hepatic blood flow of rats (55 to 80 mL min-1 kg-1) showed that nifedipine is poorly extracted by the liver (0.22 < or = EH < = 0.32). The mean absolute bioavailabilities of the p.o., i.p., and i.c. doses were 61, 90, and 100%, respectively. Assuming complete absorption of the extravascular nifedipine doses these results indicate that, in addition to hepatic extraction, substantial first-pass elimination of nifedipine occurs within the wall of the small intestine but not the colon of the rat.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Analysis of Variance
  • Animals
  • Area Under Curve
  • Biological Availability
  • Biotransformation
  • Colon / metabolism
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Intestinal Absorption
  • Liver / metabolism*
  • Male
  • Nifedipine / administration & dosage
  • Nifedipine / blood*
  • Nifedipine / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Nifedipine