The use of the suicide CYP450 inhibitor ABT for distinguishing absorption and metabolism processes in in-vivo pharmacokinetic screens.
Since drug candidates with low oral systemic exposure may be due to either or both absorption and metabolism factors, determining what factors limit the oral systemic exposure is not always obvious in a single in-vivo pharmacokinetic (PK) assay. A rapid rat in-vivo PK screen where the oxidative drug metabolism has been attenuated using the suicide CYP450 inhibitor aminobenzotriazole (ABT) is described. We have shown that the roles of absorption and metabolism for drug candidates with low oral systemic exposure can be determined by comparing the PK parameters of drug candidates orally administered to non-treated and ABT-treated rats. Propranolol, metoprolol and climetidine are used as model drugs. Propranolol and metoprolol have low oral systemic exposures in rats primarily due to metabolism factors while the oral systemic exposure of climetidine is high in rats. For propranolol and metoprolol, large increases in the systemic exposure of these drugs were observed between non-treated and ABT-treated rats. ABT appeared not to increase or decrease significantly the rate and extent of absorption or metabolism of cimetidine since that oral systemic exposure of non-treated and ABT-treated rats did not significantly change. These experiments suggest that for drug candidates with low systemic exposures in rats an observation of no change in the oral systemic exposure in ABT-treated rats when compared to the non-treated rats imply that absorption (or formulation) factors limit the systemic exposure of the drug while an increase in the systemic exposure in ABT-treated rats imply that metabolism factors limit the systemic exposure. Due to the ease of preparing and interpreting PK data from ABT-treated rats, is suggested that this assay could be used as an alternative to in vivo cannulation assays.
Caldwell
Gary W
GW
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh & McKean Roads, P.O. Box 776, Spring House, PA 19477, USA. gcaldwel@prdus.jnj.com
Ritchie
David M
DM
Masucci
John A
JA
Hageman
William
W
Cotto
Carlos
C
Hall
Jeffrey
J
Hasting
Becki
B
Jones
William
W
D000042:Absorption; D000818:Animals; D019540:Area Under Curve; D001562:Benzimidazoles / Q000493:pharmacokinetics; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000494:pharmacology*
C501044:7-fluoro-1,2-dihydro-5-(2-(N-methyl-N-(2-methoxyethyl)amino)ethyl)-3-oxo-N-(2-fluorophenyl)pyrido(1,2-a)benzimidazole-4-carboxamide hydrochloride; D001562:Benzimidazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D014230:Triazoles; C033020:1-aminobenzotriazole