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In Vivo Investigation in Pigs of Intestinal Absorption, Hepatobiliary Disposition, and Metabolism of the 5 alpha-Reductase Inhibitor Finasteride and the Effects of Coadministered Ketoconazole
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2011 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 39, no 5, 847-857 p.Article in journal (Refereed) Published
Abstract [en]

The overall aim of this detailed investigation of finasteride's pharmacokinetics (PK) and metabolism in pigs was to improve the understanding of the in vivo PK for this drug and its metabolites. Specific aims were to examine the effects of ketoconazole co-administration on the PK in three plasma compartments (the portal, hepatic and femoral veins), bile and urine and to utilize these data to in detail study the intestinal absorption, the liver extraction ratio and apply a semi-physiological based PK model to the data. The pigs received an intrajejunal dose of finasteride (0.8 mg/kg) either alone (n=5) or together with ketoconazole (10 mg/kg) (n=5), or an intravenous dose (0.2 mg/kg) (n=3). Plasma, bile and urine (collected from 0-6 hours) were analyzed with ultra performance liquid chromatography tandem mass spectrometry. Ketoconazole increased the bioavailability of finasteride from 0.36±0.23 to 0.91±0.1 (p<0.05) and the terminal half-life from 1.6±0.4 to 4.0±1.1 hours (p<0.05). From deconvolution it was found that the absorption rate from the intestine to the portal vein was rapid and the product of the fraction absorbed and the fraction that escaped gut wall metabolism was high (fa*FG≈1). Interestingly, the apparent absorption rate constant (k(a)) to the femoral vein was lower compared to the portal vein, probably because of binding and distribution within the liver. The liver extraction ratio was time-dependent and varied with the two routes of administration. After intrajejunal administration, from 1 6 hours the liver extraction ratio was significantly (p<0.05) reduced by the ketoconazole treatment from intermediate (0.41±0.21) to low (0.21±0.10).

Place, publisher, year, edition, pages
2011. Vol. 39, no 5, 847-857 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-149821DOI: 10.1124/dmd.110.035311ISI: 000289619600016PubMedID: 21317368OAI: oai:DiVA.org:uu-149821DiVA: diva2:405857
Available from: 2011-03-24 Created: 2011-03-24 Last updated: 2017-12-11Bibliographically approved

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