Comparative evaluation of some pharmacological properties and side effects of D-glucitol hexanicotinate (sorbinicate) and nicotinic acid correlated with the plasma concentration of nicotinic acid.

In rabbits kept on a diet containing 1 g/day cholesterol for 12 weeks, the nicotinic acid derivative sorbinicate displayed greater hypolipemic and antiatherogenic activity than an equidose of plain nicotinic acid at much lower and more constant plasma nicotinic acid levels. In normocholesterolemic rats, nicotinic acid given at a level of 300 mg/kg per dose for 3 weeks induced plasma FFA and triglyceride rebound and triglyceride accumulation in the liver and possibly in the heart (all parameters determined 24 h after the last dosing), whereas an equidose of sorbinicate was free from these effects, potentially the two most dangerous side effects of nicotinic acid. By modulating the bioavailability of nicotinic acid, sorbinicate maintains and in some cases enhances the pharmacological activity of the acid, avoiding at least some of its major side effects.

Inhibition of rabbit lung angiotensin converting enzyme by idrapril.

Idrapril, the prototype of a new class of angiotensin converting enzyme (ACE) inhibitors, competitively inhibited, with nanomolar apparent Ki, the hydrolysis of hippuryl-glycyl-glycine by rabbit lung ACE. The pre-steady-state analysis of this tight-binding inhibition showed it to be characterized by slow kinetics, but at variance with what was found for enalaprilat in the same conditions, idrapril appeared to act through a simple, single step mechanism. Kinetic Ki and k(on) and k(off) values were 470 pM, 3.0 +/- 1.5 x 10(6) M-1 sec-1 and 1.4 +/- 0.3 x 10(-3) sec-1, respectively.

Effects of cicloxilic acid on bile flow and lipid composition in rats with ethinylestradiol-induced cholestasis.

A subacute dose of ethinylestradiol reduces the bile flow and the bile salt:cholesterol and bile salt + lecithin:cholesterol molar ratios in the rat. An acute dose of cis-2-hydroxy-2-phenyl-cyclohexanecarboxylic acid (cicloxilic acid) 50 mg kg-1 i.v. normalizes these parameters. These findings confirm and extend similar data in laboratory animals and in clinical trials.

High-performance liquid chromatographic method with electrochemical detection for the determination of idrapril, a novel angiotensin-converting enzyme inhibitor, in biological matrices.

A reversed-phase high-performance liquid chromatographic method for the determination of idrapril in human and rat plasma and urine and in rat tissue homogenates is described. The method is based on the electrochemical detection of idrapril without prior derivatization. Sample preparation simply consists in deproteinization with acetonitrile for plasma and tissue homogenates and in passage through a Sep-Pak C18 cartridge for urine. The limit of quantification is 12.5 ng/ml for plasma, 125 ng/g for tissues and 2.5 micrograms/ml for urine. The method is suitable for monitoring idrapril plasma pharmacokinetics in humans and its tissue distribution and urinary excretion in rats.

Pharmacokinetics and pharmacodynamics of idrapril in rats, dogs, and humans.

Idrapril is the prototype of a new class of angiotensin converting enzyme (ACE) inhibitors. Its pharmacokinetics and pharmacodynamics (plasma ACE activity) were investigated in rats, dogs (after intravenous and oral doses), and human volunteers (after oral doses). Following intravenous administration (1 mg/kg) to rats and dogs, elimination half-lives were 96 and 52 min, systemic clearance 19.6 and 9.5 ml/min kg, and volume of distribution 2.7 and 0.8 liters/kg, respectively. Pharmacokinetics appeared linear in dogs, within the dose range of 0.1-10 mg/kg. After oral administration of similar doses (approximately 2 mg/kg) in the three species studied, peak plasma concentrations were 182, 567, and 726 ng/ml; AUCs 25, 85, and 182 micrograms min/ml; and elimination half-lives 82, 54, and 174 min in rats, dogs, and healthy volunteers, respectively. Absolute oral bioavailability was calculated to be approximately 24% in rats and dogs. Idrapril did not bind to plasma proteins of the species studied. Plasma ACE was fully inhibited following oral administration of approximately 2 mg/kg in rats and humans, but in dogs maximal inhibition did not exceed 85%. Duration of action, measured as time for ACE to recover to 70% of initial activity, was approximately 5, 3, and 22 hr in rats, dogs, and humans, respectively. Idrapril plasma levels appeared correlated in a saturable way with inhibition of plasma ACE in all three species, yielding ex vivo IC50 values of approximately 7 ng/ml for both the rat and humans, and 91 ng/ml for dogs.

Pharmacology of idrapril: a new class of angiotensin converting enzyme inhibitors.

Idrapril is the prototype of a new chemical class of angiotensin converting enzyme (ACE) inhibitors, the hydroxamic non-amino acid derivatives. Idrapril strongly inhibited rat and human plasma ACE and rabbit lung ACE (IC50: 7-12 nM) as well as the pressor response induced by angiotensin I in anesthetized rats (ED50: 63 nmol/kg i.v.). Idrapril (0.04-23 mumol/kg i.v.) lowered the blood pressure dose dependently, up to 20-35%, in different models of hypertension (sodium-depleted spontaneously hypertensive rat, two-kidney-one-clip renal hypertensive rat, and aortic-coarctated rat), its profile being similar to that of captopril in terms of potency and efficacy. Idrapril and captopril reduced the blood pressure and potentiated substance P-induced bronchoconstriction in the guinea pig to the same extent, suggesting a similar degree of ACE inhibition in the circulation. However, idrapril potentiated capsaicin-induced bronchoconstriction (a model that has been related to the liability of ACE inhibitors to produce cough in patients) less effectively than captopril. We conclude that effective ACE inhibition in vitro and in vivo can be obtained with this novel class of compounds.