Studies on the metabolic fate of m17055, a novel diuretic (5): pharmacokinetics and pharmacodynamics of unchanged drug in rat and dog after intravenous administration of M17055.
The pharmacokinetics and pharamacodynamics of M17055, a novel diuretic were studied after a single intravenous administration to rats and dogs, the two species used in the pharmacological and toxicological studies. No gender dependent response to systemic exposure was observed at the high dose level in rats, in agreement with the determined LD(50). A gender difference in urinary excretion of M17055, however, was clearly observed in rats. The slower elimination and the lower total body clearance (CLtot) values of M17055 in dogs reflect the difference of the no-effect level (NOEL) between rats (0.1 mg/kg) and dogs (0.03 mg/kg) well. The diuretic response was well correlated with the urinary M17055 excretion rate by fitting to a sigmoid E(max) model in both rats and dogs. The derived ER(50) value of M17055 in dogs was approximately 10 times less than that reported for furosemide, suggesting that the intrinsic potency of M17055 is equal to or higher than those of other powerful loop diuretics. Although diuretic sensitivity was considered to be lower in dogs than in rats, the higher amount of M17055 reaching the dog kidney is likely to compensate for this. The diuretic response in female rats was predictable by using the pharmacodynamic parameters derived from male rats. These results show that the apparent high diuretic potency and the other pivotal observations for M17055 found in the pharmacological and toxicological studies can be rationalized by the pharmacokinetic and pharmacodynamic properties of the unchanged compound.
Nakajima
Hiroyuki
H
Drug Metabolism and Pharmacokinetics Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan. h-naka@mochida.co.jp
Naba
Hiroyasu
H
Nakanishi
Takeshi
T
Nakai
Kiyohiko
K
Watanabe
Takanori
T
Ida
Keiichi
K
Ohzawa
Nobuo
N