Prodrug ACE Inhibitors
To the Editor:
In a recent issue of Circulation, Brown and Vaughan1 reviewed ACE inhibitors. They stated that captopril and lisinopril are active drugs and listed 7 other ACE inhibitors approved in the United States that are inactive prodrugs until metabolized in the liver. More information should be provided on this clinically important subject.
First, the package inserts say that liver disease may impair activation of prodrugs. This may apply to liver congestion due to heart failure. Second, 7% to 10% of the white population are so-called poor metabolizers, who have impaired activation of prodrugs.2 Percentages for other ethnic groups are unknown, but genetic polymorphism is expected to vary pharmacokinetics.3 Third, the review discusses drug interactions but omits the fact that erythromycins, antidepressants, ketoconazole,4 and even grapefruit juice5 inhibit liver enzymes needed to activate prodrugs.
These facts suggest many of our patients may be taking medication of impaired potency. Clinicians have no access to blood assays for the active metabolites. Data necessary to clarify these issues are not available. Therefore, when hypertension or heart failure fails to respond adequately to a prodrug ACE inhibitor, we should consider a trial of captopril or lisinopril.
- Copyright © 1998 by American Heart Association
As Dr Rabinowitz states, and as indicated in our article, the majority of ACE inhibitors are administered as prodrugs, which are then deesterified by the gut and liver. Although liver disease may impair activation of the prodrug, this is not of much therapeutic importance because the dose of drug can be titrated upward, and the parent compound is not toxic. With respect to drug interactions, there are no data suggesting interactions with drugs that affect either CYP2D6 (the P450 cited for which 7% to 10% of whites are poor metabolizers) or CYP3A4 (ketoconazole, erythromycins, and grapefruit juice).