Enalapril: Pharmacokinetic/Dynamic Inferences for Comparative Developmental Toxicity
Enalapril is an antihypertensive drug of the class of angiotensin-converting enzyme inhibitors (ACEI) used in pregnancy for treatment of pre-existing or pregnancy-induced hypertension. The use of ACE inhibitors (drugs that act directly on the renin-angiotensin system) during the second and third trimester of pregnancy in humans is associated with specific fetal and neonatal injury. The syndrome, termed "ACEI fetopathy" in humans, does not appear to have a similar counterpart in experimental animals. The present paper reviews pharmacokinetic and pharmacodynamic aspects of enalapril that are physiologically important during pregnancy and intrauterine development in humans and in experimental animal species with the aim of better understanding the comparability of the manifestations of enalapril developmental toxicity in animals and humans. The human fetus is at a disadvantage with regard to in utero enalapril exposure in comparison to some of the animal species for which gestational pharmacokinetic data are available. Important reasons for the higher vulnerability of the human fetus are its accessibility by enalapril and the earlier (relative to animal species) intrauterine development of organ systems that are specific targets of ACEI pharmacologic effect (the kidney and the renin-angiotensin system). In humans, these systems develop prior to calcarial ossification at the end of first trimester of pregnancy. The specific pharmacodynamic action of enalapril on these systems during fetal life is the chief determinant of the etiology and pathogenesis of ACEI fetopathy in humans. In contrast, in most of the studied animal species, these target systems are not developed until close to term when the fetus is relatively more mature (and therefore less vulnerable), so that the window of vulnerability is narrower in comparison to the human. Among animal species, the best concordance in fetal pharmacodynamics to the human is seen in the rhesus monkey, but further studies are necessary to determine if similar developmental pathology is induced in this animal model upon repeated administration of the drug during the relevant period of intrauterine development. Animal-human concordance of developmental toxicity is least likely in the rat because of greater disparities in enalapril availability to the fetus and the relative development of the kidney and skeletal ossification compared to that in humans.