Bama miniature pigs (Sus scrofa domestica) as a model for drug evaluation for humans: comparison of in vitro metabolism and in vivo pharmacokinetics of lovastatin.
The objective of this study was to demonstrate that Bama miniature pigs are a suitable experimental animal model for the evaluation of drugs for man. To this end, in vitro lovastatin metabolism at the minipig liver microsomal level and in vivo pharmacokinetics were studied. Results were compared with those obtained from humans. Our data indicate that the main metabolites and enzyme kinetic parameters of lovastatin metabolism are similar in pigs and humans. Triacetyloleandomycin, a specific inhibitor of human CYP3A4, inhibited the metabolism of lovastatin in pig and human liver microsomes. In addition, the pharmacokinetic parameters and absolute bioavailability suggested that the absorption and elimination of lovastatin in Bama miniature pigs were similar to those in humans. Lovastatin was distributed across many organs in pigs, but the highest levels were found in the stomach, intestines, and liver. Within 96 h, 7% and 82% of the given dose was excreted in the urine and feces, respectively. In addition, no significant species differences in the plasma protein binding ratio of lovastatin and the rates of lovastatin hydrolysis to beta-hydroxyacid lovastatin were apparent. From these results, we conclude that Bama miniature pigs are suitable for use in drug evaluation studies.
Liu
Yu
Y
Department of Laboratory Animal Science, College of Basic Medicine, Third Military Medical University, Chongqing, China.
Zeng
Ben-Hua
BH
Shang
Hai-Tao
HT
Cen
Yan-Yan
YY
Wei
Hong
H
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008148:Lovastatin / Q000378:metabolism* / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature / Q000378:metabolism*; D014217:Troleandomycin / Q000494:pharmacology
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D014217:Troleandomycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human