INITIAL PHARMACOKINETICS AND BIOAVAILABILITY OF PSC-833, A P-GLYCOPROTEIN ANTAGONIST

Resistant cancer cells have been shown to overexpress a 170-kd membran e glycoprotein called P-glycoprotein. P-glycoprotein, a product of the multidrug resistance 1 gene, functions as an energy-dependent efflux pump that decreases intracellular drug concentrations. A variety of no nchemotherapeutic agents have been shown to inhibit P-glycoprotein-dep endent drug efflux including cyclosporin. PSC 833 is a nonimmunosuppre ssive derivative of cyclosporin D with the ability to reverse multidru g resistance because of P-glycoprotein overexpression in vitro. As par t of early clinical development of PSC 833, the authors investigated t he bioavailability of an oral formulation of PCS 833. PSC 833 (3 mg/kg ) was administered as a 2-hour intravenous infusion on day 1 of the tr eatment cycle. Serial blood samples for the determination of PSC 833 w hole blood concentrations were obtained after both the intravenous and oral doses. On day 5 of the study, patients received a single oral do se (9 mg/kg) of PSC 833. A total of 14 patients were treated. The intr avenous data were best described by a two-compartment open model. The oral data also were described using a two-compartment model, with oral absorption incorporating a lag time to account for possible delays in absorption. There was large intra- and interpatient variability in th e pharmacokinetics of PSC 833 in these patients. The absolute bioavail ability of PSC 833 was 34% but ranged from 3% to 58% of the administer ed dose. The clearance (Cl) of PSC 833, in general, was consistent bet ween the two dose forms administered. The pharmacokinetic behavior of PSC 833 appears to be similar to that of cyclosporine.