Document Detail


Mechanisms of reduced maternal and fetal lopinavir exposure in a rat model of gestational diabetes.
MedLine Citation:
PMID:  21742899     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Lopinavir 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 is altered in rodent models of GDM. Because lopinavir 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 minutes after lopinavir injection. In another cohort, fetuses were serially extracted 5-60 minutes after injection. Lopinavir was quantified using LC-MS/MS. Expression of relevant transporters, like Mdr1, and Cyp3a2, which metabolizes lopinavir in rodents, was measured in maternal liver via qRT-PCR and western blot. Expression of relevant transporters was also measured in placenta via qRT-PCR. Protein binding was determined by ultrafiltration. Relative to controls, we observed dramatically reduced maternal and fetal lopinavir exposure in GDM. As compared to controls, maternal hepatic Mdr1 and Cyp3a2 were upregulated and protein binding was reduced in the GDM group. Increased Mdr1 and Cyp3a2-mediated hepatobiliary clearance, coupled with a larger unbound lopinavir fraction, is likely to have facilitated hepatic elimination, thereby decreasing maternal and fetal exposure. Not surprisingly, upregulation of Mdr1 and Cyp3a2's transcriptional regulator, pregnane X receptor, was demonstrated in maternal liver via western blot. Upregulation of Mdr1 in placentas isolated from the GDM group likely also contributed to decreased fetal exposure to lopinavir. This study provides preclinical support for an as yet unreported drug-disease (LPV-GDM) interaction.
Authors:
Greg Anger; Micheline Piquette-Miller
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-7-8
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  -     ISSN:  1521-009X     ISO Abbreviation:  -     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-7-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
University of Toronto.
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