Placental passage of angiotensin-converting enzyme inhibitors,☆☆,

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Abstract

OBJECTIVE: Placental passage of the angiotensin-converting enzyme inhibitors temocapril and enalapril was investigated in a placental perfusion model. STUDY DESIGN: In an open system a placental lobe was perfused on both the maternal and the fetal side with a blood-free medium containing the test substances plus a reference substance on the maternal side. Six placentas were perfused with temocapril and five with enalapril. The drugs were measured by gas chromatography – mass spectrometry. RESULTS: Both angiotensin-converting enzyme inhibitors crossed the human placenta in the maternal-fetal direction in similar quantities. Temocapril showed the same pharmacokinetic characteristics as enalapril. CONCLUSIONS: This was the first study to quantify the placental transfer of angiotensin-converting enzyme inhibitors. These antihypertensive agents should not be taken during pregnancy, to avoid any potential hazards to the fetus. (AM J OBSTET GYNECOL 1996;174:1450-5.)

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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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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.

0002-9378/96 $5.00 + 0 6/1/70419

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