EXTRAHEPATIC FIRST-PASS METABOLISM OF NIFEDIPINE IN THE RAT

The peroral (po) bioavailability of nifedipine is reported to range fr om about 45 to 58% in the rat; this compares favourably to human being s. The metabolism of nifedipine is similar in rats and humans (oxidati on of the dihydropyridine ring), with the liver believed to be solely responsible for the systemic clearance of the drug and the observed fi rst-pass effect after po dosing. The purpose of this study was to dete rmine 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 (ic), and intraperitoneal ( ip) routes of administration were compared to that for an intravenous (iv) dose (in each case a dose of 6 mg kg(-1) was given) using adult m ale Sprague-Dawley rats (249-311 g, n = 6 or 7/group). The geometric m ean of systemic nifedipine plasma clearance after iv dosing was 10.3 m L 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 fl ow of rats (55 to 80 mL min(-1) kg(-1)) showed that nifedipine is poor ly extracted by the liver (0.22 less than or equal to E-H less than or equal to 0.32). The mean absolute bioavailabilities of the po, ip, an d ic doses were 61, 90, and 100%, respectively. Assuming complete abso rption of the extravascular nifedipine doses these results indicate th at, in addition to hepatic extraction, substantial first-pass eliminat ion of nifedipine occurs within the wall of the small intestine but no t the colon of the rat. (C) 1997 by John Wiley & Sons, Ltd.