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Research ArticleArticle

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Gregory J. Anger and Micheline Piquette-Miller
Drug Metabolism and Disposition October 2011, 39 (10) 1850-1859; DOI: https://doi.org/10.1124/dmd.111.040626
Gregory J. Anger
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Micheline Piquette-Miller
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Abstract

Lopinavir (LPV) is the preferred HIV protease inhibitor in pregnancy, but it is unknown if gestational diabetes mellitus (GDM) affects its disposition. Hepatic protein expression and plasma protein binding are altered in rodent models of GDM. Because LPV is influenced by hepatic transporters and metabolic enzymes and is highly protein bound, it was hypothesized that streptozotocin-induced GDM would alter its disposition. Maternal and fetal tissues were collected from GDM rats and controls 45 min after LPV injection. In another cohort, fetuses were serially extracted 5 to 60 min after injection. LPV was quantified using liquid chromatography tandem mass spectrometry. Expression of relevant transporters, such as Multidrug resistance protein 1 (Mdr1), and cytochrome P450 3a2 (Cyp3a2), which metabolizes LPV in rodents, was measured in maternal liver via quantitative reverse transcriptase polymerase chain reaction and Western blot analysis. Expression of relevant transporters also was measured in placenta via quantitative reverse transcriptase polymerase chain reaction. Protein binding was determined by ultrafiltration. Relative to controls, we observed dramatically reduced maternal and fetal LPV exposure in GDM. Compared with controls, maternal hepatic Mdr1 and Cyp3a2 were up-regulated, and protein binding was reduced in the GDM group. Increased Mdr1- and Cyp3a2-mediated hepatobiliary clearance, coupled with a larger unbound LPV fraction, is likely to have facilitated hepatic elimination, thereby decreasing maternal and fetal exposure. Not surprisingly, up-regulation of Mdr1 and Cyp3a2's transcriptional regulator, pregnane X receptor, was demonstrated in maternal liver via Western blot analysis. Up-regulation of Mdr1 in placentas isolated from the GDM group likely also contributed to decreased fetal exposure to LPV. This study provides preclinical support for an as yet unreported drug-disease (LPV-GDM) interaction.

Footnotes

  • This work was supported by an operating grant from the Canadian Institutes of Health Research [Grant 57688]. G.J.A. is the recipient of a Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award, which is also from the Canadian Institutes of Health Research.

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

    doi:10.1124/dmd.111.040626.

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

  • ABBREVIATIONS:

    LPV
    lopinavir
    RTV
    ritonavir
    MDR1
    multidrug resistance protein 1
    AAG
    α1-acid glycoprotein
    GDM
    gestational diabetes mellitus
    STZ
    streptozotocin
    MRP2
    multidrug resistance-associated protein 2
    BCRP
    breast cancer resistance protein
    PXR
    pregnane X receptor
    GD
    gestational day
    LC-MS/MS
    liquid chromatography tandem mass spectrometry
    FFA
    free fatty acid
    qRT-PCR
    quantitative reverse transcriptase polymerase chain reaction
    Ct
    crossover threshold
    OD
    optical density
    ANOVA
    analysis of variance
    AUC
    area under the concentration-versus-time curve.

  • Received May 13, 2011.
  • Accepted July 8, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
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Research ArticleArticle

LOPINAVIR EXPOSURE IN A RAT MODEL OF GESTATIONAL DIABETES

Gregory J. Anger and Micheline Piquette-Miller
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1850-1859; DOI: https://doi.org/10.1124/dmd.111.040626

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Research ArticleArticle

LOPINAVIR EXPOSURE IN A RAT MODEL OF GESTATIONAL DIABETES

Gregory J. Anger and Micheline Piquette-Miller
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1850-1859; DOI: https://doi.org/10.1124/dmd.111.040626
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