Polyinosinic/polycytidylic acid-mediated changes in maternal and fetal disposition of lopinavir in rats

Abstract

Maintenance of optimal lopinavir (LPV) concentration is essential for effective antiretroviral therapy and prevention of mother-to-child transmission of human immunodeficiency virus. However, little is known about the effects of inflammation on the pharmaco-kinetics of this protease inhibitor and drug transporter substrate, particularly during gestation. Our objective was to study the effect of polyinosinic/polycytidylic acid [poly(I: C)], a viral mimetic, on key maternal drug transporters, and to examine the effect on maternal and fetal disposition of LPV in rats. Poly(I: C) (5.0 mg/kg i.p.) or saline vehicle was administered to pregnant Sprague-Dawley rats on gestational days 17-18. At 24 hours postinjection, all rats were administered LPV (10 mg/kg i.v.), and plasma and tissues were collected at 5-120 minutes postadministration. Plasma interferon-γ (IFN-γ) levels were measured by enzyme-linked immunosorbent assay, and transporter expression was measured via real-time polymerase chain reaction. Maternal plasma, hepatic, placental, and fetal LPV concentrations were determined by liquid chromatography-tandem mass spectrometry. Administration of poly(I: C) induced IFN-γ plasma levels and downregulated the expression of several important ATP-binding cassette (ABC) drug efflux transporters in the placenta and liver of pregnant rats, compared with controls (P < 0.05). Maternal LPV plasma concentration and area under the concentration-versus-time curve were significantly increased in the poly(I: C) group. Plasma protein binding was also significantly higher in poly(I: C)-treated rats. Pronounced increases in hepatic, placental, and fetal LPV tissue: unbound plasma concentrations were seen in the poly(I: C) group; however, absolute tissue concentrations were not changed. Since the majority of commonly used and clinically important antiretro-viral drugs are known to be ABC transporter substrates, inflammation-mediated changes in transporter expression could affect their maternal disposition and fetal exposure.