Inhibition of renal clearance of furosemide by pentopril, an angiotensin-converting enzyme inhibitor

Abstract

The pharmacokinetic interaction between pentopril (250 mg) and furosemide (40 mg) was studied in 12 normal healthy volunteers after oral administration of each drug alone and in combination. No significant changes in any pharmacokinetic parameters of pentopril or its active metabolite (CGS 13934) were observed on coadministration of furosemide. In contrast, pentopril induced significant changes in disposition of furosemide. Pentopril decreased renal clearance (CLR) of furosemide by 54% and the fraction excreted unchanged in urine also decreased by 55%. However, such decrease in CLR of furosemide was compensated by a simultaneous increase in glucuronidation (by 200%), resulting in a slight increase in systemic clearance (decreased AUC). Systemic bioavailability of furosemide appears to be unchanged in the presence of pentopril (0.46 vs. 0.41). No effect of pentopril on plasma protein binding of furosemide was detected. In spite of the decreased CLR and urinary excretion rate of furosemide, the urinary output (1749 vs. 1774 ml/6 hr) and Na+ excretion (757 vs. 816 mEq/6 hr) remained almost unchanged. These findings suggest that total furosemide (unchanged and glucuronide) might contribute to diuresis and natriuresis rather than the unchanged furosemide alone. Because of unchanged pharmacodynamic effect, such pharmacokinetic interaction may not require any dosage adjustment for furosemide on pentopril coadministration.