SITE-DIFFERENTIAL GASTROINTESTINAL ABSORPTION OF BENAZEPRIL HYDROCHLORIDE IN HEALTHY-VOLUNTEERS

The absorption of benazepril-HCl (BZPH), an orally active angiotensin- converting enzyme (ACE) inhibitor, in various regions of the gastroint estinal (GI) tract was investigated using an intestinal intubation tec hnique. Thirteen subjects completed this single-dose, three-phase sequ ential crossover study. The drug (20 mg) was administered either as a 4-hr colonic infusion (COLON) or as a small intestinal infusion (SI) i n the first two phases and as an oral bolus solution (ORAL) in the thi rd phase, with a 2-week washout between each treatment. Serial plasma and urine samples were collected for up to 4 days after dosing. BZPH a nd its active metabolite benazeprilat (BZPL) were determined using a g as chromatography/mass spectrometry method. BZPH was absorbed rapidly into the bloodstream (T-max = 0.5 hr after ORAL). Absorption was also rapid for SI, with a postinfusion half-life (0.57 hr) nearly identical to that for ORAL (0.59 hr). The absorption rate after COLON was much slower (lower C-max and longer T-max) compared to that after SI, and t he apparent half-life (1.7 hr) was prolonged. SI delivered 90%, wherea s COLON delivered 23%, of the drug into the systematic circulation as compared to ORAL. BZPL was rapidly formed upon drug absorption. The me tabolite-to-drug AUC ratios were comparable for SI and ORAL (8.9 vs 9. 7), indicating that first-pass metabolism of BZPH was neither saturabl e nor input rate dependent. The metabolite-to-drug AUC ratio was reduc ed for COLON (5.0), indicating that the mechanism of absorption of BZP H in the colon may be different than that after SI and ORAL. Urinary r ecovery data were consistent with plasma data. It can be concluded tha t COLON delivered a smaller amount of drug at a slower absorption rate to the body than either SI or ORAL.