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Pharmaceutics 2017, 9(4), 49; doi:10.3390/pharmaceutics9040049

The Role of PXR Genotype and Transporter Expression in the Placental Transport of Lopinavir in Mice

1
Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada
2
Reata Pharmaceuticals, Irving, TX 75063, USA
*
Author to whom correspondence should be addressed.
Received: 2 October 2017 / Revised: 19 October 2017 / Accepted: 20 October 2017 / Published: 24 October 2017
(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)
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Abstract

Lopinavir (LPV), an antiretroviral protease inhibitor frequently prescribed in HIV-positive pregnancies, is a substrate of Abcb1 and Abcc2. As differences in placental expression of these transporters were seen in Pregnane X Receptor (PXR) −/− mice, we examined the impact of placental transporter expression and fetal PXR genotype on the fetal accumulation of LPV. PXR +/− dams bearing PXR +/+, PXR +/−, and PXR −/− fetuses were generated by mating PXR +/− female mice with PXR +/− males. On gestational day 17, dams were administered 10 mg/kg LPV (i.v.) and sacrificed 30 min post injection. Concentrations of LPV in maternal plasma and fetal tissue were measured by LC-MS/MS, and transporter expression was determined by quantitative RT-PCR. As compared to the PXR +/+ fetal units, placental expression of Abcb1a, Abcc2, and Abcg2 mRNA were two- to three-fold higher in PXR −/− fetuses (p < 0.05). Two-fold higher fetal:maternal LPV concentration ratios were also seen in the PXR +/+ as compared to the PXR −/− fetuses (p < 0.05), and this significantly correlated to the placental expression of Abcb1a (r = 0.495; p < 0.005). Individual differences in the expression of placental transporters due to genetic or environmental factors can impact fetal exposure to their substrates. View Full-Text
Keywords: antiretrovirals; transporters; P-glycoprotein; breast cancer resistance protein; multidrug resistance associated protein; gene regulation; protease inhibitor; Pregnane X Receptor; placenta; knockout mice antiretrovirals; transporters; P-glycoprotein; breast cancer resistance protein; multidrug resistance associated protein; gene regulation; protease inhibitor; Pregnane X Receptor; placenta; knockout mice
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Gahir, S.S.; Piquette-Miller, M. The Role of PXR Genotype and Transporter Expression in the Placental Transport of Lopinavir in Mice. Pharmaceutics 2017, 9, 49.

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