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The pharmacokinetics, distribution and excretion of NKH477, a novel water-soluble forskolin derivative, improving acute cardiac failure, were investigated in rats and dogs after a single intravenous administration of 14C-labeled NKH477 and unlabeled NKH477. 1. After intravenous bolus administration of 14C-NKH477 (0.011 ?? 0.3 mg/kg) to male rats, the elimination half life of radioactivity in the blood ranged from 70.67 to 118.23 hr. The elimination half life of radioactivity in the blood was prolonged compared with that in the plasma, which should be attributed to binding of the radioactivity to blood cells. 2. After intravenous bolus dosing of NKH477 to male rats, plasma concentrations of unchanged NKH477 and active metabolite, M-1, declined rapidly with half lives of 0.23 and 0.25 hr, respectively. The AUC of M-1 was markedly lower than that of unchanged NKH477. 3. In dogs, the radioactivity levels in the blood and plasma declined two-exponentially following administration, and the slow elimination of the blood radioactivity, but less compared to rats, was also observed. 4. Following intravenous infusion of NKH477 for 2 hours to male dogs under anesthesia at doses ranging from 0.15 to 0.60 mg/kg/min, plasma concentrations of unchanged NKH477 and M-1 decreased with the elimination half lives of 1.57 ?? 2.36 hr. The AUC of M-1 was half as much as that of unchanged NKH477. 5. After administration to male rats, the radioactivity was rapidly and extensively distributed to the tissues except those belonging to the central nervous system. The liver showed much higher concentration of radioactivity than the other tissues. The radioactivity declined rapidly from most tissues, except the heart, blood, spleen and adrenal gland. 6. After dosing to male rats, excretion of the radioactivity in urine and feces within 144 hr was 6.4 and 90.2% of dose, respectively. In bile duct-cannulated rats, biliary and urinary excretion of radioactivity was 77.1 and 7.8% of the dose, respectively within 72 hr after administration, suggesting that the main excretory route of 14C-NKH477 is feces through bile. 7. In dogs, 78.2% of the dose was excreted into feces during 144 hr after dosing.

Metabolic Fate of NKH477. (1). Blood and Plasma Concentrations, Distribution and Excretion in Rats and Dogs after a Single Intravenous Administration.