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The disposition and urinary elimination of thioridazine 5-sulfoxide (ring sulfoxide) following subacute administration of thioridazine was investigated in control and phenobarbital (Pb) induced rats. The ring sulfoxide exists as two stereoisomeric pairs, identified by high performance liquid chromatography as fast eluting (RSF) and slow eluting (RSS) ring sulfoxide. No major differences were detected in the distribution in serum or tissue of the ring sulfoxide between control and induced animals. The ring sulfoxide accumulated in all tissues studied. RSF tissue concentrations were significantly greater than those of RSS in both groups. However, stereoselective formation and elimination of the two ring sulfoxides was not noted in either group. Pb inducible cytochrome P-450 drug metabolizing enzymes do not appear to play a major role in the biotransformation of thioridazine to the ring sulfoxide.

The disposition and elimination of 2 stereoisomeric forms of thioridazine 5-sulfoxide (ring sulfoxide) were followed for 72 hr in male Sprague-Dawley rats following the administration of a single 40 mg/kg intraperitoneal dosage. The distribution half-lives for the fast (RSF) and slow (RSS) eluting ring sulfoxides in serum were 4.40 and 3.23 min, respectively. Elimination half-lives were 1.79 and 2.06 h. Both RSF and RSS were distributed throughout the tissue in equal amounts based on HPLC analysis of the tissues. Both isomers were found in lung tissue at concentrations 10 times that for other organs. Elimination of the ring sulfoxide was complete by 72 hours except in the brain, lung and kidney. The brain, heart, liver and kidney exhibited periodicity, or recycling of both RSF and RSS during the elimination phase. Release of RSF and RSS from myocardial tissue was slower than that for all other tissues. Excretion of unchanged thioridazine 5-sulfoxide occurred via renal, and to a lesser extent, biliary mechanisms. The biliary excretion pattern suggested an enterohepatic circulation of both isomers. These results indicate a lack of stereoselectivity in the disposition and clearance of the two ring sulfoxide isomers in the animal model; results that mirror those seen in man.