Abstract
The pharmacokinetics of suplatast tosilate, (±)-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]dimethylsulfonium p-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 in vitro.
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-CH3SH(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.
2. When IPD-1151T was orally administered, IPD-1151T base and metabolites, M-1-Cys, M-1-Ac•Cys, M-1-CH3SH(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.
3. When IPD-1151T was orally administered, IPD-1151T base was mainly excreted in all examined animals.
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.
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 in vitro. 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.
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.
