In vivo, ex vivo, and in vitro effects of L-NAME and L-arginine on the metabolism of theophylline in the rabbit.
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 i.v.) 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 microM) 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.
Barakat
M
M
Department of Pharmacology, Faculty of Medicine, Université de Montréal, Québec, Canada.
El-Kadi
A O
AO
Du Souich
P
P
D000818:Animals; D019540:Area Under Curve; D001120:Arginine / Q000494:pharmacology*; D001711:Biotransformation; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006207:Half-Life; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011817:Rabbits; D013806:Theophylline / Q000493:pharmacokinetics*
D004791:Enzyme Inhibitors; D001120:Arginine; D013806:Theophylline; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester