Model for the drug-drug interaction responsible for CYP3A enzyme inhibition. II: establishment and evaluation of dexamethasone-pretreated female rats.
1. Cytochrome P450 (CYP) 3A catalysis of testosterone 6beta-hydroxylation in female rat liver microsomes was significantly induced, then reached a plateau level after pretreatment with 80 mg kg(-1) day(-1) dexamethasone (DEX) for 3 days. 2. Midazolam was mainly metabolized by CYP3A in DEX-treated female rat liver microsomes from an immuno-inhibition study, and the apparent K(m) was 1.8 microM, similar to that in human microsomes. 3. Ketoconazole and erythromycin, typical CYP3A inhibitors, demonstrated extensive inhibition of midazolam metabolism in DEX-treated female rat liver microsomes, and the apparent K(i) values were 0.088 and 91.2 microM, respectively. The values were similar to those in humans, suggesting that DEX-treated female rat liver microsomes have properties similar to those of humans. 4. After oral administration of midazolam, the plasma midazolam concentration in DEX-treated female rats significantly decreased compared with control female rats. The area under the plasma concentration curve (AUC) and elimination half-life were one-11th and one-20th of those of control female rats, respectively. 5. Using DEX-treated female rats, the effect of CYP3A inhibitors on midazolam pharmacokinetics was evaluated. The AUC and maximum concentration in plasma (C(max)) increased when ketoconazole was co-administered with midazolam. 6. It was shown that the drug-drug interaction that occurs in vitro is also observed in vivo after oral administration of midazolam. In conclusion, the DEX-treated female rat could be a useful model for evaluating drug-drug interactions based on CYP3A enzyme inhibition.
Kanazu
T
T
Developmental Research Laboratories, Shionogi & Co., LTD, Toyonaka, Osaka, Japan. takushi.kanazu@shionogi.co.jp
Yamaguchi
Y
Y
Okamura
N
N
Baba
T
T
Koike
M
M
D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone / Q000008:administration & dosage*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000008:administration & dosage; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D023421:Models, Animal; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam; D007654:Ketoconazole