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Drug metabolism of CYP3A4, CYP2C9 and CYP2D6 substrates in pigs and humans
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (The Biopharmaceutic group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2011 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 43, no 3, 89-98 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2011. Vol. 43, no 3, 89-98 p.
Keyword [en]
Verapamil, Testosterone, Pig pharmacokinetics, Dextromethorphan, In vitro metabolism, Pig mRNA expressison
National Category
Pharmaceutical Sciences Cell and Molecular Biology
Research subject
URN: urn:nbn:se:uu:diva-155943DOI: 10.1016/j.ejps.2011.03.008ISI: 000291906500001OAI: oai:DiVA.org:uu-155943DiVA: diva2:429319
Available from: 2011-07-04 Created: 2011-07-04 Last updated: 2012-05-08Bibliographically approved
In thesis
1. First-pass Intestinal Metabolism of Drugs: Experiences from in vitro, in vivo and simulation studies
Open this publication in new window or tab >>First-pass Intestinal Metabolism of Drugs: Experiences from in vitro, in vivo and simulation studies
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The bioavailability of a drug can be described as the fraction of an orally administered dose that reaches the systemic circulation and is often limited by first-pass metabolism in the gut and the liver. It is important to have knowledge about these processes since the systemic blood drug concentration is tightly connected to the effect of the drug.

The general aim of this project was to quantitatively examine the role of the intestine in relation to the liver in first-pass metabolism of orally administered drugs. The first-pass metabolism of verapamil and raloxifene was investigated in detail with in vivo, in vitro and simulation studies, using the pig as an experimental model.

The intestine contributed to the same extent as the liver to first-pass metabolism of R/S-verapamil in vivo in pigs. The S-isomer of verapamil was found in lower plasma concentrations compared to the R-isomer after oral dosing. The in vitro metabolism of verapamil in pig and human liver showed interspecies similarity and indicated equal intrinsic clearance for R- and S-verapamil. Through physiologically based pharmacokinetic modeling the stereoselectivity was explained by a combination of several processes, including enantioselective plasma protein binding, blood-to-plasma partition, and gut and liver tissue distribution. For raloxifene the intestine was the dominating organ in first-pass glucuronidation in vivo in pigs. Furthermore, the raloxifene concentration entering the intestine or the dose administered in the gut did not influence the plasma PK of raloxifene and indicated that the intestinal metabolism was not saturable with clinical relevant doses. For both verapamil and raloxifene, a time-dependent hepatic metabolism was noted with major consequences to the pharmacokinetic of the drugs.

This project has pointed out the importance of intestinal metabolism in the overall first-pass extraction of drugs and indicates that intestinal metabolism should be considered and evaluated early in drug development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 66 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 153
pharmacokinetics, metabolism, CYP3A4, CYP2C9, CYP2D6, UGT, glucuronidation, physiologically based pharmacokinetic model, modelling
National Category
Pharmaceutical Sciences
Research subject
urn:nbn:se:uu:diva-165514 (URN)978-91-554-8251-0 (ISBN)
Public defence
2012-02-24, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2012-02-03 Created: 2012-01-09 Last updated: 2012-02-15Bibliographically approved

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