RT Journal Article
SR Electronic
T1 In Vivo, Ex Vivo, and In Vitro Effects ofl-NAME and l-Arginine on the Metabolism of Theophylline in the Rabbit
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 191
OP 195
VO 25
IS 2
A1 Mouhsine Barakat
A1 Ayman O. S. El-Kadi
A1 Patrick Du Souich
YR 1997
UL http://dmd.aspetjournals.org/content/25/2/191.abstract
AB 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 ofN-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 vivoin hepatocytes of control and treated animals. In vivo, compared with control rabbits, both l-NAME andl-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 thein vitro studies, incubation of l-NAME orl-arginine with hepatocytes did not modify the biotransformation of theophylline. It is concluded thatl-NAME and l-arginine inhibit the activity of several apoenzymes of P450, the probable mechanism being a catalysis-dependent inhibition. The American Society for Pharmacology and Experimental Therapeutics