Abstract
The metabolic disposition of thymoxamine hydrochloride (thymoxamine), in paticular its pharmacokinetics and bioavailability, was investigated in rats, beagle dogs and rabbits. After oral or intravenous administration of thymoxamine to animal species, free and conjugated forms of deacetyl-thymoxamine (DAM) and deacetyl-demethyl-thymoxamine (Met-X) were detected in plasma and tissues, without unchanged thymoxamine. From examination of pharmacokinetic parameters, it is suggested that thymoxamine administered orally absorbed rapidly from gastric intestinal tract, and the disappearance rate of thymoxamine was rapid relatively. It was cleared that rats and beagle dogs were readily affected the first-pass effects, compared with human. Gastrointestinal tract absorption in rabbit was show to occur mainly form intestine and to lesser, though significant, from stomach. In tissue distribution, DAM was extremely high concentration in the kidney and liver at 15-30 min after oral administration of 100 mg/kg of thymoxamine to rats. Within 48 hr, total cumulative excretion of two metabolites in urine and feces accounted for about 94 % of dosage. Evalution of ear skin temperature in beagle dogs was caused by oral administration of 120 mg/body (14.4 mg/kg) of thymoxamine-tablets, and then minimum effective concentration of DAM in plasma was 0.5 erg/ml. Comparative studies of thymoxamine and DAM in beagle dogs, bioavailability of thymoxamine was superior to DAM. Consequently, it is concluded that thymoxamine is a prodrug to DAM, which amis at improvement in bioavilability of DAM.
