Placental passage of angiotensin-converting enzyme inhibitors☆,☆☆,★
Section snippets
MATERIAL AND METHODS
Because temocapril and enalapril are prodrugs that are metabolized in the liver into the active substances temocapril diacid and enalaprilat, respectively, perfusions were carried out with the active forms of the substances in concentrations corresponding to the plasma concentrations observed after doses effective in the treatment of mild to moderate hypertension.
Placental transfer of the antihypertensive substances was investigated with a double-sided open ex vivo perfusion model7, 8 of human
RESULTS
Each perfusion experiment consisted of 3 preperfusion sample assays and 17 maternal and 17 fetal perfusion assays. The concentrations of the ACE inhibitors are given in nanograms × milliliters−1 of the base “not of the salts” of temocapril diacid and enalaprilat. To obtain the concentration of salts, the concentrations were multiplied by approximately 1.080 for temocapril diacid hydrochloride and by 1.333 for enalaprilat maleate.
All three compounds, temocapril diacid hydrochloride, enalaprilat,
COMMENT
ACE inhibitors are competitive inhibitors of the angiotensin-converting enzyme, which catalyzes the conversion of angiotensin I to angiotensin II and the degradation of the vasodilator bradykinin. Low levels of angiotensin II have been reported in guinea pig offspring after in utero exposure to ACE inhibitors.12 However, a high concentration of angiotensin II may be physiologically necessary in the fetus and newborn to increase perfusion pressure in hypotensive states for maintenance of
Acknowledgements
We thank Dr. P. R. Robinson (Simbec Research Limited, Methyr Tydfil, United Kingdom) for the gas chromatography–mass spectrometry assays of the investigated drugs.
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Cited by (21)
Pregnancy outcome after in utero exposure to angiotensin converting enzyme inhibitors or angiotensin receptor blockers
2011, Reproductive ToxicologyCitation Excerpt :Angiotensin converting enzyme inhibitors (ACEIs) are a group of compounds used in the management of hypertension [1] and in diabetic nephropathy [2]. In vitro studies have shown that ACEIs cross the sheep [3] and human [4] placentae. There is evidence from animal studies that administration of ACEIs during pregnancy is associated with fetal toxicity and an increase in still-births [5,6].
Administration of D-alanine-[Ang-(1-7)] (A-779) prior to pregnancy in Sprague Dawley rats produces antidiuresis in late gestation
2008, Journal of the American Society of HypertensionCitation Excerpt :Unlike other antihypertensive agents including the ACE inhibitors, use of the Ang-(1-7) receptor antagonist, A-779, does not appear to have detrimental effects on fetal characteristics including the fetal size, length, or number or on maternal body weight in late gestation. Previous studies have shown that placentas perfused with the ACE inhibitors enalapril and temocapril demonstrated that both drugs can cross the human placenta in similar quantities in maternal-fetal directions23 contributing to the contraindication of such drugs in pregnancy. Infants exposed to ACE inhibitors have been shown to be at increased risk for malformations of the cardiovascular system and the central nervous system even when ACE inhibitors are administered in the first trimester of pregnancy.24
Pregnancy and Cardiovascular Disease
2004, Medical Complications During PregnancyEnalapril: Pharmacokinetic/dynamic inferences for comparative developmental toxicity
2001, Reproductive ToxicologyThe role of teratogens in neural crest development
2020, Birth Defects Research
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From the Department of Obstetrics and Gynecology, University of Vienna,athe Department of Obstetrics and Gynecology, Ludwig Maximilians-University,band the Department of Clinical Research and Biometrics, Luitpold Pharma Gmbh, Sankyo Group.c
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Reprint requests: K. Reisenberger, MD, Department of Obstetrics and Gynecology, University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
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0002-9378/96 $5.00 + 0 6/1/70419