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

Nicola F. Smith, Sridhar Mani, Erin G. Schuetz, Kazuto Yasuda, Tristan M. Sissung, Susan E. Bates, William D. Figg, Alex Sparreboom

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1709-1717
Number of pages9
JournalAnnals of Pharmacotherapy
Volume44
Issue number11
DOIs
StatePublished - Nov 2010

Fingerprint

Cytochrome P-450 CYP3A
Vinblastine
Cytoplasmic and Nuclear Receptors
Midazolam
Hep G2 Cells
Pharmacogenetics
P-Glycoprotein
Nonparametric Statistics
Reporter Genes
Microtubules
Pharmacokinetics
Western Blotting

Keywords

  • CYP3A4
  • Induction
  • NR1I2 (PXR)
  • Vinblastine

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Smith, N. F., Mani, S., Schuetz, E. G., Yasuda, K., Sissung, T. M., Bates, S. E., ... Sparreboom, A. (2010). Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2. Annals of Pharmacotherapy, 44(11), 1709-1717. https://doi.org/10.1345/aph.1P354

Induction of CYP3A4 by vinblastine : Role of the nuclear receptor NR1I2. / Smith, Nicola F.; Mani, Sridhar; Schuetz, Erin G.; Yasuda, Kazuto; Sissung, Tristan M.; Bates, Susan E.; Figg, William D.; Sparreboom, Alex.

In: Annals of Pharmacotherapy, Vol. 44, No. 11, 11.2010, p. 1709-1717.

Research output: Contribution to journalArticle

Smith, NF, Mani, S, Schuetz, EG, Yasuda, K, Sissung, TM, Bates, SE, Figg, WD & Sparreboom, A 2010, 'Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2', Annals of Pharmacotherapy, vol. 44, no. 11, pp. 1709-1717. https://doi.org/10.1345/aph.1P354
Smith NF, Mani S, Schuetz EG, Yasuda K, Sissung TM, Bates SE et al. Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2. Annals of Pharmacotherapy. 2010 Nov;44(11):1709-1717. https://doi.org/10.1345/aph.1P354
Smith, Nicola F. ; Mani, Sridhar ; Schuetz, Erin G. ; Yasuda, Kazuto ; Sissung, Tristan M. ; Bates, Susan E. ; Figg, William D. ; Sparreboom, Alex. / Induction of CYP3A4 by vinblastine : Role of the nuclear receptor NR1I2. In: Annals of Pharmacotherapy. 2010 ; Vol. 44, No. 11. pp. 1709-1717.
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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.",
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AU - Yasuda, Kazuto

AU - Sissung, Tristan M.

AU - Bates, Susan E.

AU - Figg, William D.

AU - Sparreboom, Alex

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N2 - 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.

AB - 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.

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