0090-9556/97/2502-0191-0195$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 2

In Vivo, Ex Vivo, and In Vitro Effects of L-NAME and L-Arginine on the Metabolism of Theophylline in the Rabbit

Mouhsine Barakat, Ayman O. S. El-Kadi, and Patrick Du Souich

Department of Pharmacology, Faculty of Medicine, Université de Montréal

It has been shown that selected isoforms of cytochrome P450 (P450) can generate nitric oxide from L-arginine analogs; however, the effect of L-arginine analogs on the catalytic activity of P450 remains unknown. To assess the effect of N-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) and L-arginine (150 mg/kg) on the activity of P450, these compounds were administered intravenously every 8 hr for 2 days to groups of six New Zealand rabbits. Thereafter, the biotransformation of theophylline was documented in vivo (2.5 mg/kg iv) and ex vivo in hepatocytes of control and treated animals. In vivo, compared with control rabbits, both L-NAME and L-arginine increased theophylline plasma concentrations secondary to a reduction in theophylline systemic clearance by 46% and 42% (p < 0.05), respectively. Ex vivo, the effect of L-arginine analogs on P450 activity was documented by measuring the production of 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) after incubation of theophylline (176 µM) with hepatocytes for 4 hr. L-NAME reduced the formation of 3MX, 1MU, and 1,3DMU by 42%, 45%, and 32% (p < 0.05), respectively. However, L-arginine reduced only the formation of 3MX by 34% (p < 0.05). In the in vitro studies, incubation of L-NAME or L-arginine with hepatocytes did not modify the biotransformation of theophylline. It is concluded that L-NAME and L-arginine inhibit the activity of several apoenzymes of P450, the probable mechanism being a catalysis-dependent inhibition.