Physiological modeling of altered pharmacokinetics of a novel anticancer drug, UCN-01 (7-hydroxystaurosporine), caused by slow dissociation of UCN-01 from human alpha1-acid glycoprotein.
OBJECTIVE
The extremely low clearance and small distribution volume of UCN-01 in humans could be partly due to the high degree of binding to hAGP. The quantitative effects of hAGP on the pharmacokinetics of UCN-01 at several levels of hAGP and UCN-01 were estimated in rats given an infusion of hAGP to mimic the clinical situation and a physiological model for analysis was developed.


METHODS
The plasma concentrations of UCN-01 (72.5-7250 nmol/kg i.v.) in rats given an infusion of hAGP, 15 or 150 nmol/h/kg, were measured by HPLC. Pharmacokinetic analysis under conditions assuming rapid equilibrium of protein binding and incorporating the dissociation rate was conducted.


RESULTS
The Vdss and CLtot of UCN-01 (725 nmol/kg i.v.) in rats given an infusion of hAGP, 150 nmol/h/kg, fell to about 1/250 and 1/ 700 that in control rats. The Vdss and CLtot following 72.5-7250 nmol/kg UCN-01 to rats given 150 nmol/h/kg hAGP were 63.9-688 ml/kg and 3.18-32.9 ml/h/kg, respectively, indicating non-linearity due to saturation of UCN-01 binding. The CLtot estimated by the physiological model assuming rapid equilibrium of UCN-01 binding to hAGP, was six times higher than the observed value while the CLtot estimated by the model incorporating k(off), measured using DCC, was comparable with the observed value.


CONCLUSIONS
These results suggest that the slow dissociation of UCN-01 from hAGP limits its disposition and elimination.
Fuse
E
E
Drug Development Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Sunto-Gun, Shizuoka, Japan.
Hashimoto
A
A
Sato
N
N
Tanii
H
H
Kuwabara
T
T
Kobayashi
S
S
Sugiyama
Y
Y
D000465:Algorithms; D000470:Alkaloids / Q000493:pharmacokinetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D006801:Humans; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D016014:Linear Models; D008297:Male; D008954:Models, Biological; D009961:Orosomucoid / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000031:analogs & derivatives
D000470:Alkaloids; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D009961:Orosomucoid; C054852:7-hydroxystaurosporine; D019311:Staurosporine