title: Mechanisms of reduced maternal and fetal lopinavir exposure in a rat model of gestational diabetes.
abstract: Lopinavir (LPV) is the preferred HIV protease inhibitor in pregnancy, but it is unknown if gestational diabetes mellitus (GDM) affects its disposition. Hepatic protein expression and plasma protein binding are altered in rodent models of GDM. Because LPV is influenced by hepatic transporters and metabolic enzymes and is highly protein bound, it was hypothesized that streptozotocin-induced GDM would alter its disposition. Maternal and fetal tissues were collected from GDM rats and controls 45 min after LPV injection. In another cohort, fetuses were serially extracted 5 to 60 min after injection. LPV was quantified using liquid chromatography tandem mass spectrometry. Expression of relevant transporters, such as Multidrug resistance protein 1 (Mdr1), and cytochrome P450 3a2 (Cyp3a2), which metabolizes LPV in rodents, was measured in maternal liver via quantitative reverse transcriptase polymerase chain reaction and Western blot analysis. Expression of relevant transporters also was measured in placenta via quantitative reverse transcriptase polymerase chain reaction. Protein binding was determined by ultrafiltration. Relative to controls, we observed dramatically reduced maternal and fetal LPV exposure in GDM. Compared with controls, maternal hepatic Mdr1 and Cyp3a2 were up-regulated, and protein binding was reduced in the GDM group. Increased Mdr1- and Cyp3a2-mediated hepatobiliary clearance, coupled with a larger unbound LPV fraction, is likely to have facilitated hepatic elimination, thereby decreasing maternal and fetal exposure. Not surprisingly, up-regulation of Mdr1 and Cyp3a2's transcriptional regulator, pregnane X receptor, was demonstrated in maternal liver via Western blot analysis. Up-regulation of Mdr1 in placentas isolated from the GDM group likely also contributed to decreased fetal exposure to LPV. This study provides preclinical support for an as yet unreported drug-disease (LPV-GDM) interaction.
authors: Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors: Gregory J
authors: GJ
authors: Anger
authors: Micheline
authors: M
authors: Piquette-Miller
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D016640:Diabetes, Gestational / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D061466:Lopinavir / Q000493:pharmacokinetics*; D008431:Maternal-Fetal Exchange; D008565:Membrane Proteins / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D000077297:Pregnane X Receptor; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D061466:Lopinavir; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A