In vivo use of the P450 inactivator 1-aminobenzotriazole in the rat: varied dosing route to elucidate gut and liver contributions to first-pass and systemic clearance.
The small intestine is regarded as an absorptive organ in the uptake of orally administered drugs, but also has the ability to metabolize drugs by both phase 1 and phase 2 reactions. The amount of drug that reaches the systemic circulation can be reduced by both intestinal and hepatic metabolism. 1-Aminobenzotriazole (ABT) is an irreversible inhibitor of cytochrome P450s. Through in vivo and in vitro studies, ABT has been evaluated for its utility in studying intestinal metabolism in rats. Rats have been exposed to ABT through varied routes of administration followed by p.o. and i.v. administration of midazolam (MDZ), a CYP3A substrate. The MDZ bioavailablity in rats dosed orally and in rats dosed intravenously with ABT is 58.5% and 0.7%, respectively (%F = 2.3% w/o ABT). The approximately 80-fold difference between the two groups suggests the majority of the extraction occurs in the intestine following an oral dose. To further study the utility of ABT, the antihistamine fexofenadine (Fex), which is not significantly metabolized and is a substrate for the uptake and efflux transporters, OATP and P-gp, was tested in rat. There was no change in oral or systemic exposure of Fex when animals were predosed with ABT, suggesting that ABT does not affect these transporters. These findings may lead to a better understanding of the interdependent role of absorption and metabolism and the specificity of ABT. This method should have utility in drug discovery for the identification of factors limiting oral bioavailability.
Strelevitz
Timothy J
TJ
Pfizer Inc., PGRD, Pharmacokinetics, Dynamics, and Metabolism, Eastern Point Road, Groton, CT 06340, USA.
Foti
Robert S
RS
Fisher
Michael B
MB
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D007275:Injections, Intravenous; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D014230:Triazoles; C033020:1-aminobenzotriazole