@article {Petrovicdmd.114.062315, author = {Vanja Petrovic and Micheline Piquette-Miller}, title = {Polyinosinic/Polycytidylic Acid-Mediated Changes in Maternal and Fetal Disposition of Lopinavir in Rats}, elocation-id = {dmd.114.062315}, year = {2015}, doi = {10.1124/dmd.114.062315}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Maintenance of optimal lopinavir (LPV) concentration is essential for effective antiretroviral therapy and prevention of mother-to-child transmission of HIV. 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 day 17-18. At 24 hours post-injection, all rats were administered LPV (10 mg/kg i.v.) and plasma and tissues collected at 5-120 min post-administration. Plasma IFN-γ levels were measured by ELISA and transporter expression was measured via real-time polymerase chain reaction. Maternal plasma, hepatic, placental and fetal LPV concentrations were determined by LC-MS/MS. Administration of poly(I:C) induced IFN-γ plasma levels and downregulated the expression of several important ABC drug efflux transporters in placenta and liver of pregnant rats, compared to controls (p\<0.05). Maternal LPV plasma concentration and AUC were significantly increased in 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.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2015/04/17/dmd.114.062315}, eprint = {https://dmd.aspetjournals.org/content/early/2015/04/17/dmd.114.062315.full.pdf}, journal = {Drug Metabolism and Disposition} }