US EPA

2776889 

Journal Article 

[Pharmacokinetic studies of sepimostat mesilate (FUT-187) (XI)--transfer to fetuses and sex related differences after single oral administration in rats] 

Kurotori, M; Suzuki, M; Arakawa, K; Sato, T; Tsuda, M; Karasawa, Y; Inaba, A; Seki, H; Hayashi, K; Sekine, A; Et al 

1996 

DART/TER/95003754 

30 

8 

Japanese 

6-Amidino-2-naphthyl-4-((4,5-dihydro-1H-imidazol-2-yl)amino)benzoate dimethanesulfonate (sepimostat mesilate, FUT-187), a novel protease inhibitor, is an ester of 4-((4,5-dihydro-1H-imidazol-2-yl)amino)benzoic acid (IABA) and 6-amidino-2-naphthol (AN). The transfer of radioactivity to fetuses and sex-related differences were studied after administration of (14C-AN)FUT-187 or (14C-IABA)FUT-187 to rats. 1) The radioactivity on the whole body autoradiograms was rapidly distributed to tissues, and the levels in most tissues reached maxima at 4 or 1 hr after oral administration of 30 mg/kg of (14C-AN)FUT-187 or (14C-IABA)FUT-187 to male rats. The radioactivity distributed was rapidly eliminated from tissues as plasma. No radioactivity was retained in a specific tissue. 2) A little radioactivity was distributed to fetuses on whole body autoradiograms after oral administration of 30 mg/kg of (14C-AN)FUT-187 to female rats on days 12 and 18 of pregnancy. No radioactivity was detected in fetuses after 14 hr post-dosing. The levels of radioactivity in the fetal whole body and tissues were 6% or less of that in the maternal plasma, and the distribution ratio of radioactivity per fetus was less than 0.004% of the dose at 4 hr after oral administration to female rats on day 18 of pregnancy. The radioactivity distributed was rapidly eliminated from tissues. These data indicate that the transfer of radioactivity to fetuses is very low, and the radioactivity is unlikely to retain for a long term in fetuses. The transfer of radioactivity deviated from (14C-IABA)FUT-187 in fetuses was similar to that from (14C-AN)FUT-187 after oral administration of a 30 mg/kg dose. 3) The level of radioactivity in the milk was lower than that in the plasma, and declined with a similar half-life to that in the plasma after oral administration of 30 mg/kg of (14C-AN)FUT-187 to lactating rats on day 11 after delivery. These data indicate that the transfer of radioactivity to milk is low, and the radioactivity is unlikely to retain for a long term in milk. The transfer of radioactivity deviated from (14C-IABA)FUT-187 in milk was similar to that from (14C-AN)FUT-187 after oral administration of a 30 mg/kg dose. 4) No differences were observed in the Cmax and AUC of radioactivity in the plasma between male and female rats after oral administration of 30 mg/kg of (14C-AN)FUT-187. No sex difference was also observed in the plasma after oral administration of 30 mg/kg of (14C-IABA)FUT-187. The metabolite profiles in the plasma from female rats on day 18 of pregnancy were similar to those from male rats at 4 hr after oral administration of 30 mg/kg of (14C-AN)FUT-187. These data suggest no sex differences in the disposition of FUT-187.