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

^*Corresponding author for this work

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

211 Scopus citations

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
State	Published - 1 Aug 1998
Externally published	Yes

Cite this

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.

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

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.",

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

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language = "English",

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T1 - Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human α1-acid glycoprotein

AU - Fuse, Eiichi

AU - Tanii, Hiromi

AU - Kurata, Noriaki

AU - Kobayashi, Hiroyuki

AU - Shimada, Yasuhiro

AU - Tamura, Tomohide

AU - Sasaki, Yasutsuna

AU - Tanigawara, Yusuke

AU - Lush, Richard D.

AU - Headlee, Donna

AU - Figg, William D.

AU - Arbuck, Susan G.

AU - Senderowicz, Adrian M.

AU - Sausville, Edward A.

AU - Akinaga, Shiro

AU - Kuwabara, Takashi

AU - Kobayashi, Satoshi

PY - 1998/8/1

Y1 - 1998/8/1

N2 - 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.

AB - 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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M3 - Article

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AN - SCOPUS:0032145499

SN - 0008-5472

VL - 58

SP - 3248

EP - 3253

JO - Cancer Research

JF - Cancer Research

IS - 15

ER -

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

Abstract

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