[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].
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-cyclohexyl-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 10 mg/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.
Nakazawa
M
M
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Kitayama
E
E
Adachi
T
T
Yoshida
M
M
Ishibashi
S
S
Yoshikawa
K
K
Kajihara
T
T
Iwakura
K
K
Sumi
N
N
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D004032:Diet; D005260:Female; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010648:Phenylacetates / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014549:Urinary Incontinence / Q000188:drug therapy; D014555:Urination Disorders / Q000188:drug therapy*
D010648:Phenylacetates; C105354:temiverine