Limited sampling strategy in rats to predict the inhibited activities of hepatic CYP3A.
The present study was undertaken in order to evaluate feasibility of a limited sampling strategy (LSS) to predict the systemic clearance of midazolam (MDZ), which is a hepatic CYP3A activity phenotyping probe. Groups of rats pretreated with or without serial doses of ketoconazole, which is a selective inhibitor on CYP3A, were used as training set. Linear regression analysis and a Jack-knife validation procedure were performed based on plasma MDZ concentrations at specific time points after sublingual vein injection of MDZ to establish the most informative LSS equations for accurately estimating the clearance of MDZ. Another group of rats in the same setting was used as the validation set to confirm the individual values of estimated clearance (Clest) that were derived from the predictive equations developed in the training set. LSS that were derived from one, two or three sampling times, namely 90 min, 60-90 min, 30-60-90 min and 30-60-120 min, gave the best correlation and acceptable errors between the values of observed clearance (Clobs) and Clest and were chosen to evaluate hepatic CYP3A activity. Our results supported the hypothesis that using limited plasma sampling is simpler than the usual method of estimating CYP3A phenotyping by predicting the systemic clearance of MDZ when the hepatic activity of CYP3A is reduced in the rat. This experimental design offers opportunities to reduce animal use in the study of drug metabolism.
Zhu
Xue-Hui
XH
Department of Pharmacology, Basic Medical College, Tianjin Medical University, Tianjin, China.
Jiao
Jian-Jie
JJ
Zhang
Cai-Li
CL
Lou
Jian-Shi
JS
Liu
Chang-Xiao
CX
D000759:Adjuvants, Anesthesia / Q000493:pharmacokinetics*; D023401:Animal Use Alternatives; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000097:blood*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007275:Injections, Intravenous; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar; D013047:Specific Pathogen-Free Organisms
D000759:Adjuvants, Anesthesia; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D007654:Ketoconazole