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Unpredicted Clinical Pharmacology of UCN-01 Caused by Specific Binding to Human ₁-Acid Glycoprotein

Drug Development Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka 411, Japan [E. F., H. T., N. K., H. K., S. A., T. K., S. K.]; Department of Medical Oncology, National Cancer Center Hospital, Tokyo 104, Japan [Y. Sh., T. T.]; Division of Hematology and Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba 277, Japan [Y. Sa.]; Department of Hospital Pharmacy, School of Medicine, Kobe University, Kobe 650, Japan [Y. T.]; Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892 [R. D. L., D. H., W. D. F.]; and Division of Cancer Treatment and Diagnosis, Rockville, Maryland 20852 [S. G. A., A. M. S., E. A. S.]

The pharmacokinetics of UCN-01 after administration as a 72- or 3-h infusion to cancer patients in initial Phase I trials displayed distinctive features that could not have been predicted from preclinical data. The distribution volumes (0.0796–0.158 liters/kg) and the systemic clearance (0.0407–0.252 ml/h/kg) were extremely low, in contrast to large distribution volume and rapid systemic clearance in experimental animals. The elimination half-lives (253–1660 h) were unusually long. in vitro protein binding experiments demonstrated that UCN-01 was strongly bound to human ₁-acid glycoprotein. The results suggest that unusual pharmacokinetics of UCN-01 in humans could be due, at least in part, to its specifically high binding to ₁-acid glycoprotein.

¹ To whom requests for reprints should be addressed, at Drug Development Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko, Kogyo Co., Ltd., 1188, Shimotogari, Nagaizumi-Cho, Sunto-Gun, Shizuoka 411, Japan. Phone: 81-559-89-2021; Fax: 81-559-86-7430; E-mail: takashi.kuwabara@kyowa.co.jp.

Received 3/27/98. Accepted 6/15/98.

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