Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human alpha1-acid glycoprotein.
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 alpha1-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 alpha1-acid glycoprotein.
Drug Development Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
E
E
Fuse
H
H
Tanii
N
N
Kurata
H
H
Kobayashi
Y
Y
Shimada
T
T
Tamura
Y
Y
Sasaki
Y
Y
Tanigawara
R D
RD
Lush
D
D
Headlee
W D
WD
Figg
S G
SG
Arbuck
A M
AM
Senderowicz
E A
EA
Sausville
S
S
Akinaga
T
T
Kuwabara
S
S
Kobayashi
D000470:Alkaloids / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004285:Dogs; D004334:Drug Administration Schedule; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009961:Orosomucoid / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives; D013379:Substrate Specificity
D000470:Alkaloids; D000970:Antineoplastic Agents; D009961:Orosomucoid; D012709:Serum Albumin; C054852:7-hydroxystaurosporine; D019311:Staurosporine