In vivo approach for the evaluation of mechanism-based inhibition of cytochrome P450 3A in rats.
1. There have been no reports showing that the area under the concentration-time curve (AUC) of a probe drug is elevated due to mechanism-based inhibition (MBI) of drug-metabolizing enzymes in animals. This study ascertained that mechanism-based inhibitors reported to induce drug-drug interactions (DDIs) in humans also caused MBI in rats. 2. Midazolam (MDZ), mainly metabolized by cytochrome P450 3A in rats, and mibefradil, which showed the most intense time-dependent inhibition among the inhibitors tested, were selected as the probe and the inhibitor, respectively. Following pretreatment of mibefradil at 24 h before MDZ administration in rats, the C(max) and AUC values of MDZ were significantly elevated in comparison with the control. The free plasma concentration of mibefradil was substantially lower than the IC(50) value observed in the in vitro inhibition study, suggesting that the DDI was due to MBI. 3. It is concluded that the evaluation of MBI in rats in vivo in combination with in vitro data using human enzymes could be useful to evaluate risk in clinical studies.
Sekiguchi
N
N
Pre-Clinical Research Department, Shizuoka, Japan. sekiguchinbo@chugai-pharm.co.jp
Kato
M
M
Takada
M
M
Watanabe
H
H
Higashida
A
A
Sakai
S
S
Ishigai
M
M
Aso
Y
Y
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006801:Humans; D008297:Male; D020748:Mibefradil / Q000008:administration & dosage; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008874:Midazolam / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity / Q000187:drug effects
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D020748:Mibefradil; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam