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

Sarabjit Gahir,Micheline Piquette-Miller

doi:10.3390/pharmaceutics9040049

Sarabjit Gahir, Micheline Piquette-Miller

Open Access

https://doi.org/10.3390/pharmaceutics9040049

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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.

Highlights

There are over 2 million children living with HIV and, according to UNAIDS, most of these infections were caused by mother-to-child transmission (MTCT) of the virus [1]
While numerous in vitro and ex vivo studies have explored the role of placental transporters in drug transport, relatively little is still known about their genetic, environmental, and pathophysiological regulation, or the impact that changes in transporter expression have on fetal
While numerous in vitro and ex vivo studies have explored the role of placental transporters in drug transport, relatively little is still known about their genetic, environmental, and pathophysiological regulation, or the impact that changes in transporter expression have on fetal drug exposure

Summary

Introduction

There are over 2 million children living with HIV and, according to UNAIDS, most of these infections were caused by mother-to-child transmission (MTCT) of the virus [1]. Employing a strategy of aggressive, proactive prophylaxis when managing HIV-seropositive pregnancies by the administration of Highly Active Anti-Retroviral Therapy (HAART) has brought the rate of vertical transmission down from around 25% in the absence of these interventions to less than 2% in North. The placenta is the principle gateway between the maternal and fetal systems, regulating the exchange of both endogenous and exogenous molecules. This barrier site performs a critical role in limiting the access of potentially toxic xenobiotics [4,5].

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