TOXICOKINETICS OF (±)-4-DIETHYLAMINO-1, 1-DIMETHYLBUT-2-YN-1-YL 2-CYCLOHEXYL-2-HYDROXY-2-PHENYLACETATE MONOHYDROCHLORIDE MONOHYDRATE (NS-21), A NOVEL DRUG FOR URINARY FREQUENCY AND INCONTINENCE, IN MICE AND RATS DURING 13-WEEK DIETARY ADMINISTRATION

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  • 新規頻尿・尿失禁治療剤 (±)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydtoxy-2-phenylacetate monohydrochloride monohydrate (NS-21) の13週間混餌投与下のマウスおよびラットにおけるトキシコキネティクス
  • 新規頻尿・尿失禁治療剤(+)-4-diethylamino-1,1-dimethylbut-2yn-1-yl2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21)の13週間混餌投与下のマウスおよびラットにおけるトキシコキネティクス
  • シンキ ヒンニョウ ニョウ シッキン チリョウザイ+4 diethylamin

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Abstract

Toxicokinetics of (±)-4-diethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a new drug for the treatment of urinary frequency and incontinence, were studied in mice and rats during a 13-week dietary administration to determine the toxicokinetic profiles of NS-21 and its active metabolite (±)-4-ethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cylohexyl-2-hydroxy-2-phenylacetate monohydrochloride (RCC-36) in dietary carcinogenicity studies. Male and female mice were given the drug in the diet at doses of 0(control), 30, 100 and 300 mg/kg/day, and male and female rats were given the drug at doses of 0(control), 10, 30 and 100 mg/kg/day. The chosen doses and means of administration were identical to those of a 78-week dietary carcinogenicity study in mice and 2-year dietary carcinogenicity study in rats. The plasma concentrations were measured on the first and the last day of the administration. For every treatment period, the plasma concentrations of NS-21 and RCC-36 increased with dose in mice and rats. The sum of the area under the concentration-time curve(AUC) of NS-21 and RCC-36 was 2694 to 8614 ng·hr/ml in the maximum dose of mice, and 2232 to 3593 ng·hr/ml in the maximum dose of rats through the administration period. These results show that, when compared with therapeutic dose in humans (682 ng·hr/ml at 10mg/body/day), the total maximal exposure to NS-21 and RCC-36 in the earlier dietary carcinogenicity studies were estimated to be 4 to 13 times higher in mice, and 3 to 5 times higher in rats.

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