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 nonlinearity in the pharmacokinetics of the drug. An attractive feature of draflazine is that the specific target site binding characteristics can be determined easily by simultaneously measuring plasma and whole blood concentrations of the drug. Measured drug concentrations following various infusion rates and infusion durations were used to develop a model in which the interrelated blood-plasma distribution, elimination, and specific target site binding of draflazine were incorporated simultaneously. The estimated binding (dissociation) constant Kd was 0.57 ng/ml plasma and the maximal specific erythrocyte binding capacity (BmaxRBC) was 163 ng/ml RBC. The maximal specific binding capacity to the tissues (Bmaxtissue) was estimated to be about 1 mg. The estimated volume of the central compartment (Vplasma + tissue fluids) 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. The time required to reach steady-state plasma concentrations of draflazine decreased with an increasing infusion rate. Time profiles of the plasma concentrations were not always representative for the time profiles of the specific target site (RBC) occupancy of draflazine, but the t1/2,z in plasma paralleled that of the drug at target sites. The apparent Vd and the t1/2,z decreased with increasing single doses whereas the total CL remained constant. The recovery of draflazine was also dose dependent and increased with increasing doses. Finally, the total CL and apparent Vd of the first dose were greater than those of the second dose of draflazine.
Snoeck
E
E
Janssen Research Foundation, Beerse, Belgium. esnoeck@pharsight.com
Jacqmin
P
P
Van Peer
A
A
Danhof
M
M
D001667:Binding, Competitive; D002316:Cardiotonic Agents / Q000097:blood / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D006400:Hematocrit; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D033703:Nucleoside Transport Proteins; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests
D002316:Cardiotonic Agents; D002352:Carrier Proteins; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; D010879:Piperazines; C072040:draflazine