The P-glycoprotein antagonist PSC 833 increases the plasma concentrations of 6α-hydroxypaclitaxel, a major metabolite of paclitaxel

Purpose: Overexpression of P-glycoprotein (Pgp) is one mechanism of drug resistance in cancer chemotherapy. A Phase I trial was conducted using PSC 833, a Pgp antagonist, in combination with paclitaxel in patients with refractory cancer. The objective of this study was to assess the effect of PSC 833 on the metabolism of paclitaxel and characterize the differences in 6α-hydroxypaclitaxel pharmacokinetics. In addition, we examined the possibility of enhanced cytotoxicity of paclitaxel by the coexistence of 6α-hydroxypaclitaxel. Experimental Design: Patients received paclitaxel 35 mg/m²/day by continuous intravenous infusion (CIVI) × 4 days without PSC 833 in cycle 1 and escalating doses of paclitaxel (13.1, 17.5, or 21.3 mg/m²/day CIVI × 4 days) with 5 mg/kg PSC 833 by mouth every 6 h × 7 days in cycle 2. Plasma samples were analyzed for both paclitaxel and its major metabolite with high -performance liquid chromatography methods. Using human liver microsomes, we studied the effect of PSC 833 on the metabolism of paclitaxel. In addition, the in vitro cytotoxicity of 6α-hydroxypaclitaxel alone and in combination with paclitaxel was evaluated. Results: Twenty-one of 22 patients had a metabolite peak (6α-hydroxypaclitaxel) observed in the chromatogram of plasma samples from cycle 2 when they received paclitaxel in combination with PSC 833. This metabolite was not detectable in plasma obtained during the first cycle when they received paclitaxel without PSC 833. During cycle 2, the mean concentrations of 6α-hydroxypaclitaxel and paclitaxel were 0.10 ± 0.074 and 0.079 ± 0.041 μg/ml, respectively. A moderate association was observed between total bilirubin and 6α-hydroxypaclitaxel concentrations (P = 0.015, r = 0.52; n = 21). Human liver microsome experiments showed that a PSC 833 concentration as high as 10 μm did not affect the production of 6α-hydroxypaclitaxel. Paclitaxel cytotoxicity in HL60 and K562 human leukemia cells was increased in the presence of noncytotoxic concentrations of 6α-hydroxypaclitaxel. Conclusions: PSC 833 increases the plasma concentration of 6α-hydroxypaclitaxel during paclitaxel therapy. Inhibition of cytochrome P-450 3A4 by PSC 833 may explain this in part, although other mechanisms cannot be excluded.