Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.
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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
Drug Enzyme Kind Organism Pharmacological Action Actions Vinblastine Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorInducerDetails Vindesine Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Food Interactions
Drug Interaction Vindesine Exercise caution with grapefruit products. Vindesine is metabolized by CYP3A4, and grapefruit inhibits CYP3A4 metabolism, which may increase vindesine serum levels. Vindesine Exercise caution with St. John's Wort. Vindesine is metabolized by CYP3A4 and this herb induces CYP3A4 metabolism, which may reduce vindesine serum levels.