Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human α1-acid glycoprotein

Eiichi Fuse; Hiromi Tanii; Noriaki Kurata; Hiroyuki Kobayashi; Yasuhiro Shimada; Tomohide Tamura; Yasutsuna Sasaki; Yusuke Tanigawara; Richard D. Lush; Donna Headlee; William D. Figg; Susan G. Arbuck; Adrian M. Senderowicz; Edward A. Sausville; Shiro Akinaga; Takashi Kuwabara; Satoshi Kobayashi

Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human α₁-acid glycoprotein

Eiichi Fuse, Hiromi Tanii, Noriaki Kurata, Hiroyuki Kobayashi, Yasuhiro Shimada, Tomohide Tamura, Yasutsuna Sasaki, Yusuke Tanigawara, Richard D. Lush, Donna Headlee, William D. Figg, Susan G. Arbuck, Adrian M. Senderowicz, Edward A. Sausville, Shiro Akinaga, Takashi Kuwabara, Satoshi Kobayashi

Research output: Contribution to journal › Article › peer-review

193 Citations (Scopus)

Abstract

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 α₁-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 α₁-acid glycoprotein.

Original language	English
Pages (from-to)	3248-3253
Number of pages	6
Journal	Cancer Research
Volume	58
Issue number	15
Publication status	Published - 1998 Aug 1
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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Fuse, E., Tanii, H., Kurata, N., Kobayashi, H., Shimada, Y., Tamura, T., Sasaki, Y., Tanigawara, Y., Lush, R. D., Headlee, D., Figg, W. D., Arbuck, S. G., Senderowicz, A. M., Sausville, E. A., Akinaga, S., Kuwabara, T., & Kobayashi, S. (1998). Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human α₁-acid glycoprotein. Cancer Research, 58(15), 3248-3253.

Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human α₁-acid glycoprotein. / Fuse, Eiichi; Tanii, Hiromi; Kurata, Noriaki; Kobayashi, Hiroyuki; Shimada, Yasuhiro; Tamura, Tomohide; Sasaki, Yasutsuna; Tanigawara, Yusuke; Lush, Richard D.; Headlee, Donna; Figg, William D.; Arbuck, Susan G.; Senderowicz, Adrian M.; Sausville, Edward A.; Akinaga, Shiro; Kuwabara, Takashi; Kobayashi, Satoshi.

In: Cancer Research, Vol. 58, No. 15, 01.08.1998, p. 3248-3253.

Research output: Contribution to journal › Article › peer-review

Fuse, Eiichi ; Tanii, Hiromi ; Kurata, Noriaki ; Kobayashi, Hiroyuki ; Shimada, Yasuhiro ; Tamura, Tomohide ; Sasaki, Yasutsuna ; Tanigawara, Yusuke ; Lush, Richard D. ; Headlee, Donna ; Figg, William D. ; Arbuck, Susan G. ; Senderowicz, Adrian M. ; Sausville, Edward A. ; Akinaga, Shiro ; Kuwabara, Takashi ; Kobayashi, Satoshi. / Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human α₁-acid glycoprotein. In: Cancer Research. 1998 ; Vol. 58, No. 15. pp. 3248-3253.

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abstract = "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 α1-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 α1-acid glycoprotein.",

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