A combined specific target site binding and pharmacokinetic model to explore the non-linear disposition of draflazine

The capacity-limited high-affinity target site binding of draflazine to the nucleoside transporters located on the erythrocytes is a source of nonline arity in the pharmacokinetics of the drug. An attractive feature of draflaz ine is that the specific target site binding characteristics can be determi ned easily by simultaneously measuring plasma and whole blood concentration s of the dug. Measured drug concentrations following various infusion rates and infusion durations were used to develop a model in which the interrela ted blood-plasma distribution, elimination, and specific target site bindin g of draflazine were incorporated simultaneously. The estimated binding (di ssociation) constant K-d was 0.57 ng/ml plasma and the maximal specific ery throcyte binding capacity (B-maxRBC) was 163 ng/ml RBC. The maximal specifi c binding capacity to the tissues (B-maxtissue) was estimated to be about 1 mg. The estimated volume of the central compartment (Vplasma + tissue flui ds) was 12.9 L and the total intrinsic CL was 645 ml/min. After validation, the model was used to further investigate the impact of the specific high- affinity target site binding of draflazine on its disposition in plasma. Th e time required to reach steady-state plasma concentr ations of draflazine decreased with an increasing infusion rate. Time profiles of the plasma con centrations were not always representative for the time profiles of the spe cific target site (RBC) occupancy of draflazine, but the t(1/2,z) in plasma paralleled that of the drug at target sites. The apparent V-d and the t(1/ 2,z) decreased with increasing single doses whereas the total CL remained c onstant. The recovery of draflazine was also dose dependent and increased w ith increasing doses. Finally, the total CL and apparent V-d of the first d ose were greater than those of the second dose of draflazine.