DETERMINATION OF BIOAVAILABILITY AND SYSTEMICALLY AVAILABLE FRACTIONSOF DRUGS UNDERGOING REVERSIBLE METABOLISM - APPLICATION TO ULFINYL)ETHOXY]-N-[2-(DIETHYLAMINO)ETHYL]BENZAMIDE AND ITS SULFIDE AND SULFONE METABOLITES IN RATS

Methods are discussed which permit the calculation of the bioavailabil ity (F) and fraction of an oral dose entering the central circulation (f) of a drug and its interconversion metabolite. The interrelationshi ps between the F and f and between the F and systemically available fr actions afforded by reversible metabolism are also derived and describ ed. The application of these principles is illustrated by the pharmaco kinetic analysis of ulfinyl)ethoxy]-N-[2-(diethylamino)ethyl]benzamide (ML-1035, 1) and its sulfide (2) and sulfone (3) metabolites in rats. Like intravenous ML-1035, ML-1035 administered orally underwent metab olic interconversion with 2 but not with 3 in this species. Both ML-10 35 and 2 were absorbed rapidly and are pharmacologically active. On av erage, 8.3 and 13% of an oral dose (152.4 mu mol/kg) of ML-1035 were b ioavailable as ML-1035 and its sulfide metabolite, respectively, while 23 and 65% of a molar equivalent dose of the sulfide metabolite were bioavailable as either compound, respectively. Thus, the sulfide metab olite is better absorbed than ML-1035 in rats. Following oral administ ration of either ML-1035 or 2, the systemically available fractions of both compounds were weakly to moderately influenced by the reversible metabolism process in rats. Moreover, the bioavailability of the sulf one metabolite was very poor (2.5-4%) following separate oral administ ration of ML-1035, 2, and 3.