COMPARED PROPERTIES OF TRANDOLAPRIL, ENALAPRIL, AND THEIR DIACID METABOLITES

The effects of 14-day trandolapril or enalapril treatment of spontaneo usly hypertensive rats (SHRs) were studied on blood pressure and angio tensin-converting enzyme (ACE) activity measured ex vivo in various or gans, Both ACE inhibitors caused dose-dependent decreases in blood pre ssure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respect ively. However, comparison of ACE inhibitory activities of the diacid forms of trandolapril and enalapril, i.e., trandolaprilat and enalapri lat, measured in vitro on various tissues, showed that trandolaprilat was only three- to fivefold more active than enalaprilat. To understan d the reasons for such discrepancies between ex vivo effects of ACE in hibitors and in vitro actions of their diacid metabolites, we measured the lipophilicities of the compounds and investigated the possibility that trandolapril could display an ACE inhibitory effect by itself. T randolaprilat was found to be far more lipophilic than enalaprilat, as shown by reverse-phase high-performance liquid chromatography studies performed at pH 7.4 (log k(W)(7.4) = 1.487 vs. 0.108). In addition, t randolapril was practically as active in vitro as its diacid metabolit e (IC50 = 2.5 vs. 1.35 nM) in inhibiting ACE activity in the aorta, wh ereas enalapril was practically devoid of any effect (IC50 = 240 nM). Measurements of relative affinities of inhibitors or metabolites for p urified human renal ACE showed that trandolapril displayed about 20% o f the affinity of its diacid metabolite (IC50 = 15 VS. 3.2 nM); enalap rilat affinity (34 nM) was within the same range as those of trandolap ril and trandolaprilat, whereas enalapril displayed a very low affinit y for the purified enzyme (IC50 = 50 mu M) It appears that several fac tors, including differences in potency of diacid compounds in inhibiti ng ACE, lipophilicity, and potency of the prodrugs to directly inhibit ACE, may account for the greater potency of trandolapril treatment co mpared with that of enalapril in decreasing blood pressure and inhibit ing tissue ACE activity.