Comparison of the transplacental transfer of enalapril, captopril and losartan in sheep.
1. The transplacental transfers of three drugs (enalapril, captopril and losartan) which block the renin angiotensin system and have different lipophilicities were studied in chronically catheterized foetal sheep (125-139 days gestation). 2. The ability of the foeto-placental unit to convert enalapril to enalaprilat was studied in two chronically catheterized foetuses. Enalapril (3 mg kg-1, 7.9 mumol kg-1) given i.v. to the foetuses abolished the foetal pressor response to 5 micrograms angiotensin I (AI) in one foetus and attenuated the pressor response in the other. 3. Enalapril (100 mg, 5.7 mumol kg-1) given i.v. to the ewe (n = 5) abolished the maternal pressor response to 2.5 micrograms AI (n = 1) and attenuated the maternal pressor response to 5 micrograms AI (n = 5, P < 0.001). The foetal pressor response to 5 micrograms AI (n = 2) and 10 micrograms AI (n = 3) did not change. The maternal and foetal pressor responses to angiotensin II (AII; n = 5) did not change. 4. Foetal pressor responses to 5 micrograms AI (n = 1) and 10 micrograms AI (n = 2) were attenuated within 11 min of their mothers (n = 3) being given i.v. captopril (15 mg, 1.5 mumol kg-1). Foetal pressor responses to 5 micrograms AII (n = 1) and to 10 micrograms AII (n = 2) did not change. 5. Losartan (100 mg, kg-1, 21.7 mumol kg-1) given i.v. to the foetus (n = 9) attenuated the foetal pressor response to 5 micrograms AII (P < 0.001) but the maternal pressor response to 5 micrograms AII did not change. 6. Losartan (100 mg, 21.7 MICROmol kg-1) given i.v. to the ewe (n = 5) attenuated the maternal pressor response to 5 microg AII (P <0.002) but the foetal pressor response to 5 microg AII did not change.7. It is concluded that the foeto-placental unit of the sheep can metabolize enalapril to enalaprilat.Captopril readily crosses the sheep placenta but enalapril and losartan do not. Thus, the transplacental transfer of these drugs does not parallel their lipid solubilities. Furthermore the results show that AT1 receptors are important in mediating the vasoconstrictor effects of AII in the foetus.
Stevenson
K M
KM
School of Physiology and Pharmacology, University of New South Wales, Syndey, Australia.
Gibson
K J
KJ
Lumbers
E R
ER
D000803:Angiotensin I / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000493:pharmacokinetics*; D004656:Enalapril / Q000493:pharmacokinetics*; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D019808:Losartan; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D012756:Sheep; D013777:Tetrazoles / Q000493:pharmacokinetics*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D004656:Enalapril; D000803:Angiotensin I; D002216:Captopril; D019808:Losartan