Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2.
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.
Clinical Pharmacology Program, Medical Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
Nicola F
NF
Smith
Sridhar
S
Mani
Erin G
EG
Schuetz
Kazuto
K
Yasuda
Tristan M
TM
Sissung
Susan E
SE
Bates
William D
WD
Figg
Alex
A
Sparreboom
D000328:Adult; D000368:Aged; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D000090702:Constitutive Androstane Receptor; D003524:Cyclosporins / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008874:Midazolam / Q000378:metabolism; D008875:Middle Aged; D041681:NIH 3T3 Cells; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D014747:Vinblastine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D000090702:Constitutive Androstane Receptor; D003524:Cyclosporins; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; C000625853:Nr1i2 protein, mouse; C000716328:Nr1i3 protein, mouse; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014747:Vinblastine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C070272:valspodar; D008874:Midazolam