Pharmacokinetics of free and total platinum species after short-term infusion of cisplatin.

Abstract

Pharmacokinetic studies were performed in ten patients who received short-term (4-15-min) infusions of cisplatin. Computerized nonlinear least-squares analysis (NLIN) and an adapted curve-stripping approach (CSTRIP) were used to characterize total-platinum concentration-time curves. The overall curves showed a rapid initial phase and a prolonged terminal phase, separated by a phase with secondary peaks attributed to the existence of an enterohepatic recirculation. Up to Day 5, NLIN analysis revealed three exponential phases, with half-lives of 14.4 mins, 273.7 mins, and 5.3 days, respectively. However, a significant consistent divergence (P less than 0.005) was found between the observed and predicted curves during the intermediate phase, not justifying the use of an exponential function during this phase. The shape of the intermediate curve was strongly suggestive of a second influx in the plasma compartment, the amount of which was estimated by the CSTRIP approach (1.4% +/- 0.5% of the administered dose). Free-platinum levels declined in a biphasic manner (half-lives: 9.7 +/- 0.2 and 40.4 +/- 2.5 mins; n = 3). After administration of 100 mg/m2 of cisplatin, maximum platinum levels in rbcs ranged from 0.51 to 0.58 micrograms/ml and were reached within 90-150 mins. Thereafter, rbc platinum levels declined in a biphasic fashion, with a terminal half-life, for the interval Days 5-15, of 36-47 days. The binding of platinum to both plasma and proteins and rbcs in vitro (using patients' own blood) was slow, biphasic, and irreversible.