Altered Pharmacokinetics of a Novel Anticancer Drug, UCN-01, Caused by Specific High Affinity Binding to alpha sub(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 affinity binding of UCN-01 to human alpha sub(1)-acid glycoprotein (AGP) (Fuse et al., Cancer Res., 58: 3248-3253, 1998). To confirm whether its binding to human AGP actually changes the in vivo pharmacokinetics, we have studied the alteration in its pharmacokinetics after simultaneous administration of human AGP to rats: (a) the protein binding of UCN-01 was evaluated by chasing its dissociation from proteins using dextran-coated charcoal. The UCN-01 remaining 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 plasma ( similar to 20%), were