Pharmacokinetics and pharmacodynamics of a novel protein kinase inhibitor,UCN-01

Purpose: 7-Hydroxystaurosporine (UCN-01) is a potent protein kinase inhibit or and is being developed as a novel anticancer agent. We describe here its pharmacokinetics and pharmacodynamics in experimental animals. Methods: Th e pharmacokinetics of UCN-01 were studied following intravenous (i.v.) admi nistration to mice, rats and dogs at doses of 1-9, 0.35-3.5 and 0.5 mg/kg, respectively. We also studied the pharmacodynamics of UCN-01 (9 mg/kg per d ay) during and after five consecutive i.v. administrations to nude mice bea ring xenografted human pancreatic tumor cells (PSN-1). The concentrations o f UCN-01 in plasma and tumor were mess-erred by HPLC using a fluorescence d etector. Results: UGN-01 in plasma after i.v. administration was eliminated biphasically in mice and rats, and triphasically in dogs. The elimination half-lives in mice, rats and dogs were 3.00-3.98, 4.02-4.46 and 11.6 h, res pectively. The total clearance (Cl-total) values in mice, rats and dogs wer e high (1.93-2.64, 2.82-3.86 and 0.616 1/h per kg, respectively). The hepat ic clearance (Cl-hepatic) in rats represented 54.0-81.3% of Cl-total. The v olumes of distribution at steady-state in mice, rats and dogs were large (7 .89-8.42, 13.0-16.9 and 6.09 1/kg, respectively). These pharmacokinetic par ameters were dose-independent in mice and mts. UCN-01 produced significant inhibition of tumor growth during five consecutive i.v. administrations in mice bearing the xenografted PSN-1 cells, and the inhibitory effect continu ed for 3 days after the final administration. UCN-01 concentrations in tumo r tissue were much higher than those in the plasma, and the ratio of tumor to plasma concentrations was about 500 at 24 h after live consecutive doses . Conclusions: The pharmacokinetic studies showed that UCN-01 has a high cl earance and large distribution volume in various experimental animals, and its disposition is linear over the range of doses tested. The pharmacodynam ic study showed that UCN-01 is distributed at much higher concentrations in tumor than those in plasma and that it significantly inhibits tumor growth . The high distribution of UCN-01 into tumor cells may contribute to the po tent inhibition of tumor growth in vivo.