Metabolism of [ 14C]-quazodine in the rat, dog, and man

Abstract

The pharmacokinetics of [ 14C]-quazodine, a new bronchodilator, were examined in man and dog. Absorption, metabolism, and excretion of quazodine were studied in the rat, dog, and man, while distribution of the drug was measured in rats. After iv dosage, clearance of unchanged drug from plasma was rapid in both dogs and man and followed a biexponential decay curve in accordance with the equation C p = Ae − αt + Be − βt . A good fit between the actual data and the computer-generated curves was obtained employing a nonlinear regression analysis computer program. After po administration quazodine was rapidly absorbed in both man and dog, a peak plasma concentration being observed at 0.5 hr in man and at 1 hr in dogs. The drug did not localize in cerebrospinal fluid of dogs. Radioactivity was found in all tissues of rats at 1 hr after oral dosage, and no evidence for extreme drug localization or prolonged retention was found in any tissue including brain. In rats, 71.9% of the dose was recovered in urine and 14.2% in feces during the first 3 days after dosing. The 72-hr recoveries in dog urine and feces were 61.4 and 25.8%, whereas in humans these values were 84.1 and 1.1%, respectively. The major pathway for metabolism of quazodine in man, and to a lesser extent in the dog and rat, was by demethylation at the 7-position of the quinazoline ring-system followed by conjugation with glucuronic acid or sulfate. The glucuronide conjugate accounted for 78.0% of the radioactivity in human urine, 45.1% in dog, and 27.4% in rat urine. The amount of radioactivity present as the sulfate conjugate was 3.1, 15.3, and 10.5% in human, dog, and rat urine, respectively.