Absorption and excretion of thioridazine and mesoridazine in man

Tritium labeled thioridazine and mesoridazine were given to four schizophrenic subjects to determine if differences in reported clinical potency of these two drugs could be explained by different rates of absorption and excretion. Mesoridazine was found to have earlier peak blood levels and lower fecal excretion. However, the blood and fecal differences were too small to be an adequate explanation for the differences in clinical potency suggesting that the rate of metabolic degradation is a more likely explanation for the potency difference. Thioridazine differs from other phenothiazines by containing two sulfur atoms. Thioridazine is metabolized by oxidative demethylation, oxidation at both sulfur atoms to sulfoxides and sulfones and by hydroxylation in the ring followed by glucuronide formation. Monosufoxides, disulfoxide and disufone have been found in the urine and bile of rats after thioridazine administration by inverse isotope dilution analysis. Neither the ring sulfoxide nor the disulfone show significant pharmacological activity, but activity is shown by the side chain monosulfoxide, mesoridazine. In fact it has been postulated that mesoridazine is the active form of thioridazine. Mesoridazine when compared on an equal dose basis to thioridazine is more potent in anti-emotional and hypotensive effects and produces more extrapyramidal symptoms. Since oxidation of the ring sulfur would be expected to decrease potency, it has been theorized that a portion of thioridazine is oxidized within the ring prior to the oxidation of the side chain sulfur atom thus effectively decreasing the potential activity of thioridazine. Thioridazine studies in rats have shown greater excretion in the urine and bile of the side chain sulfoxide than of the ring sulfoxide or of unchanged thioridazine. The difference in potency of these two compounds could alternatively be a result of differences in absorption, reabsorption after biliary excretion or the rate of urinary excretion. The metabolic pathways of mesoridazine in the human are essentially unknown. Because of this, we thought it worthwhile to determine if the difference in potency between thioridazine and mesoridazine is also related to differences in the rate of excretion and absorption. Because phenothiazines are found in extremely low plasma concentrations, we used radioactive compounds to perform this study.