Dataset Information

Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.

ABSTRACT:

Background

Several microtubule targeting agents are capable of inducing CYP3A4 via activation of the pregnane X receptor (PXR; NR1I2).

Objective

To evaluate the CYP3A4 induction potential of vinblastine both clinically and in vitro and determine the involvement of the nuclear receptors NR1I2 and the constitutive androstane receptor (NR1I3).

Methods

Midazolam pharmacokinetics were evaluated in 6 patients who were enrolled in a Phase 1/2 study of infusional vinblastine given in combination with the ABCB1 (P-glycoprotein) antagonist valspodar (PSC 833) and received the CYP3A4 phenotyping probe midazolam on more than 1 occasion. Genotyping was conducted in CYP3A4, CYP3A5, and ABCB1 to rule out potential pharmacogenetic influences. Clinical data were followed-up by Western blotting and reporter assays in HepG2 and NIH3T3 cells treated with vinblastine over a dose range of 150-4800 ng/mL for 48 hours.

Results

In 6 patients with cancer, vinblastine increased the median (95% CI) clearance of the CYP3A4 phenotyping probe midazolam from 21.7 L/h (12.6 to 28.1) to 32.3 L/h (17.3 to 53.9) (p = 0.0156, Wilcoxon signed-rank test). No obvious effect of polymorphisms in CYP3A4, CYP3A5, and ABCB1 on midazolam clearance was observed. In vitro, vinblastine induced CYP3A4 protein. Furthermore, cell-based reporter gene assays using transiently transfected HepG2 and NIH3T3 cells indicated that vinblastine (150-4800 ng/mL) weakly activated human and mouse full-length NR1I2, but had no influence on NR1I3.

Conclusions

Collectively, these findings suggest that vinblastine is able to induce CYP3A4, at least in part, via an NR1I2-dependent mechanism, and thus has the potential to facilitate its own elimination and cause interactions with other CYP3A4 substrates.

SUBMITTER: Smith NF

PROVIDER: S-EPMC3100585 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.

Smith Nicola F NF Mani Sridhar S Schuetz Erin G EG Yasuda Kazuto K Sissung Tristan M TM Bates Susan E SE Figg William D WD Sparreboom Alex A

The Annals of pharmacotherapy 20101019 11

<h4>Background</h4>Several microtubule targeting agents are capable of inducing CYP3A4 via activation of the pregnane X receptor (PXR; NR1I2).<h4>Objective</h4>To evaluate the CYP3A4 induction potential of vinblastine both clinically and in vitro and determine the involvement of the nuclear receptors NR1I2 and the constitutive androstane receptor (NR1I3).<h4>Methods</h4>Midazolam pharmacokinetics were evaluated in 6 patients who were enrolled in a Phase 1/2 study of infusional vinblastine given ...[more]

PMID: 20959500

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Dataset Information

Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.

Background

Objective

Methods

Results

Conclusions

Publications

Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.

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