Mode of Action: Angiotensin-Converting Enzyme Inhibition—Developmental Effects Associated With Exposure to ACE Inhibitors

Relative to species tested in laboratory studies, the human fetus displays higher vulnerability to enalapril and other angiotensin-converting enzyme inhibitors (ACEI) exhibiting a malformative syndrome that does not appear to have a similar counterpart in experimental animals. An important reason for this higher vulnerability is the earlier intrauterine development of the kidney and the renin–angiotensin–aldosterone (RAS) system in humans, organ systems that are specific targets of ACEI's pharmacological effect. In humans, these systems begin developing prior to the onset of skeletal ossification at the end of the first trimester, with continuing vulnerability throughout the pregnancy. In most animal species tested, these target systems develop close to term, when the fetus is relatively more mature and less vulnerable to the effects of developmental toxicants. For this reason, animal studies that follow standard protocols and evaluate developmental toxicity only for exposures during embryogenesis will miss developmental effects arising secondary to disruption of target systems that develop after the period of major organogenesis. Thus, although the animal mode of action (MOA) for enalapril and other ACEI is plausible in humans, differences in the timing of development of critical target organ systems, particularly the renal system and RAS, explain the absence of definitive structural abnormalities in test animals.