Heterocyclic ureas: inhibitors of acyl-CoA:cholesterol O-acyltransferase as hypocholesterolemic agents.

A series of diaryl-substituted heterocyclic ureas was prepared, and their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in cholesterol-fed animal models in vivo was examined. N-(2,6-Diisopropylphenyl)-N'-tetrazole or isoxazole-substituted heterocyclic ureas proved optimal. A carbon chain of 11-14 carbons substituted 1,3 with respect to the amine provided the optimal side chain. Substitution of the alkyl chain generally lowered activity. Tetrazole urea 2i dosed at 3 mg/kg lowered plasma total cholesterol (TC) 67% in an acute, cholesterol-fed (C-fed) rat model of hypercholesterolemia and 47% in C-fed dogs. Tetrazole 2i, dosed at 10 mg/kg, also lowered TC 52% and raised HDL cholesterol 113% in rats with pre-established hypercholesterolemia.

A pharmacodynamic and pharmacokinetic comparison of intravenous quinaprilat and oral quinapril.

Quinaprilat is the active metabolite of quinapril, an orally active angiotensin-converting enzyme (ACE) inhibitor. The dose-response and duration-of-effect after single intravenous doses of quinaprilat and placebo (part A) and after administration of oral quinapril solution and intravenous quinaprilat (part B) were assessed in a randomized, crossover study of two groups of 12 healthy volunteers. Pharmacodynamic effects of quinaprilat and oral quinapril were assessed by measurement of blood pressure changes after an infusion of angiotensin I (A-I) at a dose previously determined to produce an increase in diastolic blood pressure of 25 mmHg under standardized conditions (A-I pressor response). A clear dose-response relationship was demonstrated for quinaprilat in this pharmacodynamic model, with 0.5 mg as the lowest effective dose. Doses of 1.0 mg and higher partially suppressed A-I pressor response for at least 6 hours. Onset of action was observed within 15 minutes of intravenous administration of quinaprilat and was independent of dose, whereas peak effect and duration of action appeared to be dose related. Quinaprilat doses of 2.5 mg and 10 mg achieved approximately 50% and > 80% inhibition of the A-I pressor response, respectively. In part B, these doses of intravenous quinaprilat were compared with oral doses of quinapril previously found to produce 50% (2.5 mg) and 90% (10 mg) inhibition of the A-I pressor response. The magnitude of effect was similar after administration of 20 mg quinapril orally and 10 mg quinaprilat intravenously. Duration of action was longer, however, after administration of intravenous quinaprilat (10 mg) than after oral quinapril (20 mg), due to the higher maximum plasma concentration (Cmax) of quinaprilat. Mean area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity) of quinaprilat was similar after the 10-mg dose of intravenous quinaprilat and the 20-mg dose of oral quinapril. Based on the concentrations of quinaprilat observed in this study, the absolute bioavailability of quinapril was approximately 50%; intravenous quinaprilat should therefore produce a pharmacodynamic response similar to that obtained with oral quinapril at approximately half the dose.

Meperidine pharmacokinetics following intravenous, peroral and buccal administration in beagle dogs.

The pharmacokinetics of meperidine was studied in Beagle dogs following intravenous, peroral and buccal administration of a meperidine hydrochloride solution. The elimination half-life after I.V., P.O. and buccal routes was 0.75 +/- 0.14 hours, 0.93 +/- 0.18 hours and 0.36 +/- 0.10 hours, respectively. The volume of distribution and total clearance following I.V., P.O. and buccal administration were 2.41 +/- 0.34 L/kg and 42.5 +/- 8.9 ml/min/kg, 2.84 +/- 1.24 L/kg and 34.6 +/- 7.8 ml/min/kg, 1.01 +/- 0.52 L/kg and 34.7 +/- 8.0 ml/min/kg, respectively. The absolute bioavailability after P.O. and buccal administration was 11.0 +/- 6.8% and 11.9 +/- 6.6%, respectively. This paper discusses the observed low bioavailabilities on hypothesis of hepatic and lung first-pass effect. A hypothesis is presented to explain the delayed onset of absorption following buccal administration.