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

Purpose. The extremely low clearance and small distribution volume of UCN-0 1 in humans could be partly due to the high degree of binding to hAGP (1,2) . The quantitative effects of hAGP on the pharmacokinetics of UCN-01 at sev eral 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 nmo l/kg iv) in rats given an infusion of hAGP, 15 or 150 nmol/h/kg, were measu red by HPLC. Pharmacokinetic analysis under conditions assuming rapid equil ibrium of protein binding and incorporating the dissociation rate was condu cted. Results. The Vdss and CLtot of UCN-01 (725 nmol/kg iv) in rats given an inf usion of hAGP, 150 nmol/h/kg, fell to about 1/250 and 1/ 700 that in contro l 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 e stimated by the physiological model assuming rapid equilibrium of UCN-01 bi nding to hAGP, was six times higher than the observed value while the CLtot estimated by the model incorporating k(off) measured using DCC, was compar able with the observed value. Conclusions. These results suggest that the slow dissociation of UCN-01 fro m hAGP limits its disposition and elimination.