OV-A-4Induction of cytochrome P450 3A4 (CYP3A4) by vinblastine: Role of the nuclear receptor NR1I2

Abstract

BACKGROUND Metabolism of the anticancer agent vinblastine is mediated by CYP3A4. It has been demonstrated that other microtubule stabilizing agents such as paclitaxel are capable of inducing this enzyme via activation of NR1I2 (hPXR). Therefore, we evaluated the CYP3A4 induction potential of vinblastine both clinically and in vitro. METHODS The pharmacokinetics of the CYP3A4 phenotyping probe midazolam (i.v. bolus, 0.0145 mg/kg) were determined in 6 patients with renal cell cancer undergoing treatment with vinblastine (72-h i.v. q4w) at baseline and in cycle 3. Midazolam plasma concentrations were measured by LC/MS and clearance (CL) was derived using non-compartmental analysis. Protein expression of CYP3A4 and activation of hPXR by vinblastine were measured by Western blotting and a transactivation assay using transiently transfected HepG2 cells, respectively (Mani et al, Clin Cancer Res 11:6359, 2005). RESULTS Vinblastine increased midazolam CL on average by 60% (range, 2–317%; P=0.0156, Wilcoxon test). In vitro, vinblastine at clinically-relevant concentrations induced CYP3A4 and the hPXR-ligand binding domain, but had only weak to no effect on full length hPXR, suggesting it is only a weak activator of hPXR. CONCLUSIONS Vinblastine is able to induce CYP3A4 in vivo and thus has the potential to facilitate its own elimination and cause interactions with other CYP3A4 substrates. The mechanism of protein induction is likely to be at the level of RNA stabilization or decreased protein turnover. Clinical Pharmacology & Therapeutics (2005) 79, P35–P35; doi: 10.1016/j.clpt.2005.12.125