Purpose: 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.