Document Detail


Toxicokinetic analysis of losartan during gestation and lactation in the rat.
MedLine Citation:
PMID:  8864166     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Previous developmental and reproductive toxicity studies in rats with losartan, a potent AT1-selective angiotensin II (AII) receptor antagonist, correlated maternal treatment during gestation day (GD) 15-20 with irreversible renal abnormalities in the F1 generation (Spence et al., '95a,b). Continued treatment through lactation was also associated with increases in pup mortality and decreases in pup body weights that persisted through weaning. The studies presented here were undertaken to quantify fetal and neonatal exposure to losartan when administered to the dam by oral gavage during early gestation, late gestation, and lactation. Following daily oral dosing of 135 mg/kg/day on GD6-15, fetal drug levels were negligible. However, losartan and its active metabolite, EXP3174 (L-158,641) were readily detectable in fetal plasma on GD 20 (estimated AUC values, 50.70 and 167.70 micrograms/hr/ml, respectively) and maternal milk during lactation (1.61 and 1.67 micrograms/ml, respectively). These studies suggest that the relative increased sensitivity of the fetus as compared to the neonate for losartan-induced renal lesions is related to the degree of exposure which is dependent on the time of administration (early gestation vs. late gestation/lactation) and the route of exposure (transplacental or through the milk). Furthermore, the maximum exposure to losartan and EXP3174 correlates with the ontogeny of the renin angiotensin system on approximately GD 17 and the critical period for losartan-induced renal lesions (GD15-20). The data support the hypothesis that the observed adverse fetal and neonatal effects are pharmacologically mediated, presumably through the lack of AT1 receptor stimulation.
Authors:
S G Spence; A G Zacchei; L L Lee; C L Baldwin; R A Berna; B A Mattson; R S Eydelloth
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Teratology     Volume:  53     ISSN:  0040-3709     ISO Abbreviation:  Teratology     Publication Date:  1996 Apr 
Date Detail:
Created Date:  1997-05-23     Completed Date:  1997-05-23     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0153257     Medline TA:  Teratology     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  245-52     Citation Subset:  IM    
Affiliation:
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antihypertensive Agents / pharmacokinetics,  toxicity*
Area Under Curve
Biphenyl Compounds / pharmacokinetics,  toxicity*
Female
Imidazoles / pharmacokinetics,  toxicity*
Lactation
Losartan
Milk / chemistry
Pregnancy
Rats
Rats, Sprague-Dawley
Tetrazoles / pharmacokinetics,  toxicity*
Chemical
Reg. No./Substance:
0/Antihypertensive Agents; 0/Biphenyl Compounds; 0/Imidazoles; 0/Tetrazoles; 114798-26-4/Losartan

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


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