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Research ArticleArticle

In Vivo Investigation in Pigs of Intestinal Absorption, Hepatobiliary Disposition, and Metabolism of the 5α-Reductase Inhibitor Finasteride and the Effects of Coadministered Ketoconazole

Anna Lundahl, Mikael Hedeland, Ulf Bondesson and Hans Lennernäs
Drug Metabolism and Disposition May 2011, 39 (5) 847-857; DOI: https://doi.org/10.1124/dmd.110.035311
Anna Lundahl
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Mikael Hedeland
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Ulf Bondesson
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Hans Lennernäs
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Abstract

The overall aim of this detailed investigation of the pharmacokinetics (PK) and metabolism of finasteride in pigs was to improve understanding of in vivo PK for this drug and its metabolites. Specific aims were to examine the effects of ketoconazole coadministration on the PK in three plasma compartments (the portal, hepatic, and femoral veins), bile, and urine and to use these data to study in detail the intestinal absorption and the liver extraction ratio and apply a semiphysiological 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 to 6 h) were analyzed with ultraperformance 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 h (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 (ka) to the femoral vein was lower than that 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 to 6 h, the liver extraction ratio was significantly (p < 0.05) reduced by ketoconazole treatment from intermediate (0.41 ± 0.21) to low (0.21 ± 0.10).

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.035311.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    PK
    pharmacokinetic(s)
    M1
    ω-hydroxy finasteride
    M2
    finasteride ω-al
    M3
    finasteride-ω-oic acid
    DDI
    drug-drug interaction
    VP
    portal vein
    VH
    hepatic vein
    VF
    femoral vein
    T1
    treatment 1
    T2
    treatment 2
    UPLC
    ultraperformance liquid chromatography
    HPLC
    high-performance liquid chromatography
    NCA
    noncompartment analyses
    AUC
    area under the plasma/bile concentration-time curve
    P450
    cytochrome P450
    CL
    clearance.

  • Received July 9, 2010.
  • Accepted February 11, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (5)
Drug Metabolism and Disposition
Vol. 39, Issue 5
1 May 2011
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Research ArticleArticle

In Vivo Investigation in Pigs of Intestinal Absorption, Hepatobiliary Disposition, and Metabolism of the 5α-Reductase Inhibitor Finasteride and the Effects of Coadministered Ketoconazole

Anna Lundahl, Mikael Hedeland, Ulf Bondesson and Hans Lennernäs
Drug Metabolism and Disposition May 1, 2011, 39 (5) 847-857; DOI: https://doi.org/10.1124/dmd.110.035311

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Research ArticleArticle

In Vivo Investigation in Pigs of Intestinal Absorption, Hepatobiliary Disposition, and Metabolism of the 5α-Reductase Inhibitor Finasteride and the Effects of Coadministered Ketoconazole

Anna Lundahl, Mikael Hedeland, Ulf Bondesson and Hans Lennernäs
Drug Metabolism and Disposition May 1, 2011, 39 (5) 847-857; DOI: https://doi.org/10.1124/dmd.110.035311
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