EXTRAHEPATIC FIRST-PASS METABOLISM OF NIFEDIPINE IN THE RAT

✍ Scribed by JOHN S. GRUNDY; LISE A. ELIOT; ROBERT T. FOSTER

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 170 KB
• Volume: 18
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/(sici)1099-081x(199708)18:6<509::aid-bdd38>3.0.co;2-5

✦ Synopsis

The peroral (po) 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 ®rst-pass eect after po dosing. The purpose of this study was to determine whether intestinal metabolism also contributes to the ®rst-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 71 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 iv dosing was 10´3 mL min 71 kg 71 . 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 71 kg 71 ; which, compared to the hepatic blood ¯ow of rats (55 to 80 mL min 71 kg 71 ) showed that nifedipine is poorly extracted by the liver (0´224E H 40´32). The mean absolute bioavailabilities of the po, ip, and ic 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 ®rst-pass elimination of nifedipine occurs within the wall of the small intestine but not the colon of the rat. &1997 by John Wiley & Sons, Ltd.