Document Detail


Increased glyburide clearance in the pregnant mouse model.
MedLine Citation:
PMID:  20558597     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Glyburide (GLB) is an oral sulfonylurea, commonly used for the treatment of gestational diabetes mellitus. It has been reported that the clearance of GLB in pregnant women is significantly higher than that in nonpregnant women. The molecular mechanism by which pregnancy increases the clearance of GLB is not known, but it may be caused by increased CYP3A activity. Because liver tissue from pregnant women is not readily available, in the present study, we investigated the mechanism of such pregnancy-related changes in GLB disposition in a mouse model. We demonstrated that the systemic clearance of GLB in pregnant mice was increased approximately 2-fold (p < 0.01) compared with nonpregnant mice, a magnitude of change similar to that observed in the clinical study. Plasma protein binding of GLB in mice was not altered by pregnancy. The half-life of GLB depletion in hepatic S-9 fractions of pregnant mice was significantly shorter than that of nonpregnant mice. Moreover, GLB depletion was markedly inhibited by ketoconazole, a potent inhibitor of mouse Cyp3a, suggesting that GLB metabolism in mice is primarily mediated by hepatic Cyp3a. These data suggest that the increased systemic clearance of GLB in pregnant mice is likely caused by an increase in hepatic Cyp3a activity during pregnancy, and they provide a basis for further mechanistic understanding and analysis of pregnancy-induced alterations in the disposition of GLB and drugs that are predominantly and extensively metabolized by CYP3A/Cyp3a.
Authors:
Lin Zhou; Yi Zhang; Mary F Hebert; Jashvant D Unadkat; Qingcheng Mao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-06-17
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  38     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-19     Completed Date:  2011-01-04     Revised Date:  2011-09-13    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1403-6     Citation Subset:  IM    
Affiliation:
School of Pharmacy, University of Washington, Seattle, WA 98195, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Disease Models, Animal
Female
Glyburide / pharmacokinetics*
Hypoglycemic Agents / pharmacokinetics*
Mice
Pregnancy
Grant Support
ID/Acronym/Agency:
P50 HD044404/HD/NICHD NIH HHS; U10-HD047892/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Hypoglycemic Agents; 10238-21-8/Glyburide
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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