Altered pharmacokinetics of a novel anticancer drug, UCN-01, caused by specific high affinity binding to alpha(1)-acid glycoprotein in humans

The large species difference in the pharmacokinetics/pharmacodynamics of 7- hydroxystaurosporine (UCN-01) can be partially explained by the high affini ty binding of UCN-01 to human alpha(1)-acid glycoprotein (AGP) (Fuse et al. , Cancer Res., 58: 3248-3253, 1998), To confirm whether its binding to huma n AGP actually changes the in vivo pharmacokinetics, we have studied the al teration in its pharmacokinetics after simultaneous administration of human AGP to rats: (a) the protein binding of UCN-01 was evaluated by chasing it s dissociation from proteins using dextrancoated charcoal. The UCN-01 remai ning 0.1 h after adding dextran-coated charcoal to human plasma or AGP was similar to 80%, although the values for other specimens, except monkey plas ma (similar to 20%), were <1%, indicating that the dissociation from human AGP was specifically slower than from other proteins: and (b) the pharmacok inetics of UCN-01 simultaneously administered with human AGP has been deter mined. The plasma concentrations after i.v. administration of UCN-01 with e quimolar human AGP were much higher than those after administration of UCN- 01 alone. The steady-state distribution volume and the systemic clearance w ere reduced to about 1/100 and 1/200, respectively. Human AGP thus reduced the distribution and elimination of UCN-01 substantially, On the other hand , dog AGP, which has a low binding affinity for UCN-01, did not change the pharmacokinetics of UCN-01 so much. Furthermore, human AGP markedly reduced the hepatic extraction ratio of UCN-01 from 0.510 to 0.0326. Also, human A GP (10 mu M) completely inhibited the initial uptake of UCN-01 (1 mu M) int o isolated rat hepatocytes, whereas the uptake of UCN-01 was unchanged in t he presence of human serum albumin (10 mu M). In conclusion, the high degre e of binding of UCN-01 to human GP causes a reduction in the distribution a nd clearance, resulting in high plasma concentrations in humans.