title: 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 pharmacokinetics 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 antiretroviral drugs are known to be ABC transporter substrates, inflammation-mediated changes in transporter expression could affect their maternal disposition and fetal exposure.
authors.affiliation: Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vanja
authors.initials: V
authors.lastname: Petrovic
authors.affiliation: Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada m.piquette.miller@utoronto.ca.
authors.forename: Micheline
authors.initials: M
authors.lastname: Piquette-Miller
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D005333:Fetus / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D007369:Interferon Inducers / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D061466:Lopinavir / Q000493:pharmacokinetics*; D010920:Placenta / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D017320:HIV Protease Inhibitors; D007369:Interferon Inducers; D061466:Lopinavir; D007371:Interferon-gamma; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D011070:Poly I-C