Pharmacokinetic studies of Suplatast tosilate (IPD-1151T). (III): Species differences of Suplatast tosilate (IPD-1151T) and its metabolic pathways.
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The pharmacokinetics of suplatast tosilate, (±)-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]dimethylsulfonium <I>p</I>-toluenesulfonate(IPD-1151T) after oral and intravenous administration was studied in the mice, rats, guinea pigs, dogs and monkeys. In order to clarify the metabolic pathways in detail, we examined (±)-4-[3-ethoxy-2-hydroxypropoxylacrylanilide (M-1) disposition after intravenous administration and the stability of IPD-1151T <I>in vitro</I>.<BR> 1. The maximum plasma levels of unchanged IPD-1151T base (IPD-1151T base) in the dog was the highest among examined animals and was about 10 times higher than that in rats. Area under the concentration time curve(AUC)of IPD-1151T base in the dog was the hightst, too. In the plasma, metabolites, (±)-4-(3-ethoxy-2-hydroxypropoxy)propionanilide cysteine conjugate (M-1-Cys), (±)-4-(3-ethoxy-2-hydroxypropoxy)propionanilide mercapturic acid conjugate (M-1-Ac•Cys), (±)-4-(3ethoxy-2-hydroxypropoxy)-[3-(methylsulfinyl)propion]anilide (M-1-CH<SUB>3</SUB>SH(S→O) derived from glutathione conjugate were observed in all examined animals. Contrary to, after intravenous dosing, IPD-1151T base was mainly observed while metabolites accounted only for a small quantity of M-1 in plasma in mice, rats and dogs. This results suggested that orally dosed IPD-1151T base was subjected to the first pass effects.<BR> 2. When IPD-1151T was orally administered, IPD-1151T base and metabolites, M-1-Cys, M-1-Ac•Cys, M-1-CH<SUB>3</SUB>SH(S→O) derived from glutathione conjugate were excreted in urine. Sum of urinary excreted IPD-1151T base and its metabolite were different among all species.<BR> 3. When IPD-1151T was orally administered, IPD-1151T base was mainly excreted in all examined animals.<BR> 4. When IPD-1151T was orally or intravenously administered to the bile duct cannulated rats, the major biliary product was M-1-Cys and excreted IPD-1151T base accounted for a small quantity.<BR> 5. We have studied urinary metabolites after intravenous or intraportal infusion of IPD-1151T in the rat and the stability of IPD-1151T base in the small intestine and small intestinal juice <I>in vitro</I>. Based on these results, postulated metabolic pathways are as followe : orally administered IPD-1151 T was partially metabolized to M-1 in small intestine, and both IPD-1151T base and M-1 were absorbed. IPD-1151T base was excreted in the urine as an unchanged product, while M-1 was metabolized to glutathione conjugate and their further metabolites and excreted in urine.<BR> 6. Serum protein binding of IPD-1151T base was very low. Serum protein binding of M-1 was higher than that of IPD-1151T base and its species-related differences in protein binding were observed.
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