title: Drug metabolism of CYP3A4, CYP2C9 and CYP2D6 substrates in pigs and humans.
abstract: Pigs are becoming increasingly used as a test animal both in pharmacological and toxicological assessment of new drug compounds. For interspecies comparisons and predictions it is important to characterize the expression and function of membrane transport and enzymatic proteins in pigs, particularly at a mechanistic level which will make extrapolation of observation between pig and man to be made with more confidence. The major objective of this report was to increase the integrative knowledge of drug metabolism in pigs and to compare with corresponding data from human liver microsomes. This was done by using human substrates of CYP3A4 (verapamil and testosterone), CYP2C9 (diclofenac) and CYP2D6 (dextromethorphan). In addition, the mRNA expression of important drug metabolizing enzymes and carrier-mediated transporters were assessed in intestine and liver tissues from pigs. It was shown that CYP3A4 activity is quantitatively comparable between the two species but data suggest that qualitative differences may exist. Verapamil showed similar metabolism pattern as in humans and the CYP3A4 inhibitor ketoconazole was able to inhibit the depletion of both R- and S-verapamil. A correlation between individual pig CYP3A mRNA expression and in vivo hepatic extraction ratio was established which indicates that CYP3A is the major determinant factor in both pigs and humans. However, investigations of the metabolism of testosterone resulted in qualitative different metabolite pattern between pigs and humans. The metabolism of diclofenac was very low in pig liver microsomes and did not correlate to corresponding activity in human liver microsomes. In contrast dextromethorphan exhibited a very extensive and rapid metabolism in pig liver microsomes compared to human data. Together with previously determined gene expression data it confirms that CYP2D6 substrates will be very rapidly metabolized in pigs. The mRNA data increased the knowledge of the interindividual variability and the relative expression of different enzymes and transporters in pig intestine and liver. In conclusion, this study has increased the understanding of similarities and differences between pig and human biotransformation of drugs by providing new data for four different model compounds.
authors: Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden.
authors: Helena Anna
authors: HA
authors: Thörn
authors: Anna
authors: A
authors: Lundahl
authors: Johannes Antonius
authors: JA
authors: Schrickx
authors: Paul Alfred
authors: PA
authors: Dickinson
authors: Hans
authors: H
authors: Lennernäs
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D003915:Dextromethorphan / Q000378:metabolism; D004008:Diclofenac / Q000378:metabolism; D015870:Gene Expression; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007583:Jejunum / Q000201:enzymology*; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D013045:Species Specificity; D013552:Swine; D013739:Testosterone / Q000378:metabolism*; D014700:Verapamil / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D065692:Cytochrome P-450 CYP3A Inhibitors; D012333:RNA, Messenger; D004008:Diclofenac; D013739:Testosterone; D003915:Dextromethorphan; D014700:Verapamil; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase; D007654:Ketoconazole