Gender differences in toxicokinetics, liver metabolism, and plasma esterase activity: observations from a chronic (27-week) toxicity study of enalapril/diltiazem combinations in rats.

Diltiazem (DTZ), a calcium channel blocker, and enalapril (EN), an angiotensin-converting enzyme inhibitor, are being developed as combination therapy for cardiovascular disease. A toxicokinetic evaluation of EN and DTZ drug levels during a 27-week toxicity study used an enzyme assay to measure EN and an HPLC assay to measure DTZ, deacetylated DTZ (DAD), and desmethyl DTZ (DMD). EN exposure during drug week 7 was proportional to dose and without dispositional gender differences. However, gender differences in DTZ and metabolite plasma profiles were dramatic. For example, female DTZ Cmax values were roughly 15-20% of males; DAD plasma Cmax values were roughly 3- to 10-fold greater; and the desmethyl metabolite, DMD, was roughly 2- to 10-fold lower. Sodium fluoride added to samples taken during drug week 26 to inhibit plasma esterase activity did not alter DTZ plasma profiles, suggesting that gender differences in DTZ and metabolite plasma levels were not caused by sample degradation. Liver esterase activity in treated rats was significantly greater (p > 0.05) than controls, whereas plasma activity was not affected. Female plasma and liver esterase activities were roughly 3- and 5-fold greater than males (p < 0.002), respectively, which may explain the low DTZ and high DAD plasma levels we measured. These results indicate that liver and plasma esterase activity is much greater in female rats and may be responsible for the differences in drug and metabolite plasma profiles relative to males. In addition, chronic coadministration of EN/DTZ may modestly increase liver esterase activity.