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

Article Details

Citation

Smith NF, Mani S, Schuetz EG, Yasuda K, Sissung TM, Bates SE, Figg WD, Sparreboom A

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

Ann Pharmacother. 2010 Nov;44(11):1709-17. doi: 10.1345/aph.1P354. Epub 2010 Oct 19.

PubMed ID
20959500 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
VinblastineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
VindesineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
Food Interactions
DrugInteraction
VindesineExercise caution with grapefruit products. Vindesine is metabolized by CYP3A4, and grapefruit inhibits CYP3A4 metabolism, which may increase vindesine serum levels.
VindesineExercise caution with St. John's Wort. Vindesine is metabolized by CYP3A4 and this herb induces CYP3A4 metabolism, which may reduce vindesine serum levels.