In vivo inhibition of oxidative drug metabolism by, and acute toxicity of, 1-aminobenzotriazole (ABT). A tool for biochemical toxicology.
One hour following intravenous pretreatment of rats with 50 mg/kg of the cytochrome P-450 suicide substrate 1-aminobenzotriazole (ABT), the metabolism of phenacetin to acetaminophen is inhibited completely [B. A. Mico et al., Drug Metab. Dispos. 15, 274 (1987)]. Here we report an examination of the time-course of inhibition of phenacetin elimination by ABT, a demonstration of dose-dependent inhibition of phenacetin and antipyrine clearances by ABT, and an examination of the acute toxicity of ABT in rats, as well as the effect of ABT on phenacetin metabolism in beagles. After a 1-, 12-, 24- or 36-hr pretreatment of rats with ABT (50 mg/kg, i.v.), the clearance of phenacetin was decreased 85, 88, 81 and 48%, respectively, from control values. Twelve hours after intraperitoneal pretreatment of rats with 0.3, 1.0, 5.0, 20, and 50 mg/kg of ABT, the total systemic clearance of phenacetin was suppressed 39, 47, 60, 75, and 79%, respectively, from control values. The clearance of intravenously administered antipyrine was decreased 38 and 66% after a 12-hr intraperitoneal pretreatment of rats with 10 or 50 mg/kg of ABT. In rats, no hematological, clinical chemistry, macroscopic, or microscopic abnormalities were detected 1, 2, 3, and 9 days after a single i.v. dose of ABT (50 mg/kg). A 1-hr pretreatment of beagles with ABT (20 mg/kg) decreased the clearance of intravenous phenacetin 50% and completely prevented the formation of acetaminophen. These results demonstrate that ABT pretreatment causes long-lasting inhibition of oxidative drug metabolism without disruption of normal physiological processes. Profound inhibition of oxidation in two species suggests that ABT may have general utility as an inhibitor of oxidative drug metabolism in biochemical pharmacology and toxicology studies.
Mico
B A
BA
Department of Drug Metabolism, Smith Kline & French Laboratories, Philadelphia, PA 19101.
Federowicz
D A
DA
Ripple
M G
MG
Kerns
W
W
D000082:Acetaminophen / Q000493:pharmacokinetics; D000818:Animals; D000983:Antipyrine / Q000493:pharmacokinetics; D001711:Biotransformation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008297:Male; D010084:Oxidation-Reduction; D010615:Phenacetin / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D014230:Triazoles / Q000494:pharmacology* / Q000633:toxicity
D014230:Triazoles; C033020:1-aminobenzotriazole; D000082:Acetaminophen; D010615:Phenacetin; D000983:Antipyrine