Physiological modeling of altered pharmacokinetics of a novel anticancer drug, UCN-01 (7-hydroxystaurosporine), caused by slow dissociation of UCN-01 from human [alpha]^sub 1^-acid glycoprotein

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 t...

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Bibliographic Details
Published in:Pharmaceutical research 2000-05, Vol.17 (5), p.553
Main Authors: Fuse, Eiichi, Hashimoto, Akitoshi, Sato, Natsuko, Tanii, Hiromi
Format: Article
Language:English
Subjects:
Acids
Binding sites
Cancer
Cell cycle
Cyclin-dependent kinases
Electrons
Equilibrium
Glycoproteins
Kinases
Liver
Pharmacokinetics
Physiology
Plasma
Proteins
Signal transduction
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Summary: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. 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. 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. These results suggest that the slow dissociation of UCN-01 from hAGP limits its disposition and elimination.
ISSN:0724-8741
1573-904X