Toxicokinetic analysis of losartan during gestation and lactation in the rat.
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.
Spence
S G
SG
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Zacchei
A G
AG
Lee
L L
LL
Baldwin
C L
CL
Berna
R A
RA
Mattson
B A
BA
Eydelloth
R S
RS
D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D019540:Area Under Curve; D001713:Biphenyl Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D007093:Imidazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D007774:Lactation; D019808:Losartan; D008892:Milk / Q000737:chemistry; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000633:toxicity*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D019808:Losartan