TOXICOKINETIC ANALYSIS OF LOSARTAN DURING GESTATION AND LACTATION IN THE RAT

Previous developmental and reproductive toxicity studies in rats with losartan, a potent AT(1)-selective angiotensin II (AII) receptor antag onist, correlated maternal treatment during gestation day (GD) 15-20 w ith irreversible renal abnormalities in the F-1 generation (Spence et al., '95a,b). Continued treatment through lactation was also associate d with increases in pup mortality and decreases in pup body weights th at persisted through weaning. The studies presented here were undertak en to quantify fetal and neonatal exposure to losartan when administer ed to the dam by oral gavage during early gestation, late gestation, a nd lactation. following daily oral dosing of 135 mg/kg/day on GD6-15, fetal drug levels were negligible. However, losartan and its active me tabolite, EXP3174 (L-158,641) were readily detectable in fetal plasma on GD 20 (estimated AUC values, 50.70 and 167.70 mu g/hr/ml, respectiv ely) and maternal milk during lactation (1.61 and 1.67 mu g/ml, respec tively). These studies suggest that the relative increased sensitivity of the fetus as compared to the neonate for losartan-induced renal le sions is related to the degree of exposure which is dependent on the t ime of administration (early gestation vs. late gestation/lactation) a nd the route of exposure (transplacental or through the milk). Further more, the maximum exposure to losartan and EXP3174 correlates with the ontogeny of the renin angiotensin system on approximately GD 17 and t he critical period for losartan-induced renal lesions (GD15-20). The d ata support the hypothesis that the observed adverse fetal and neonata l effects are pharmacologically mediated, presumably through the lack of AT(1) receptor stimulation. (C) 1996 Wiley-Liss, Inc.