Skip to Content
Merck
  • The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke's encephalopathy.

The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke's encephalopathy.

Drug metabolism and disposition: the biological fate of chemicals (2014-07-27)
Qiang Zhang, Yan Zhang, Sharon Diamond, Jason Boer, Jennifer J Harris, Yu Li, Mark Rupar, Elham Behshad, Christine Gardiner, Paul Collier, Phillip Liu, Timothy Burn, Richard Wynn, Gregory Hollis, Swamy Yeleswaram
ABSTRACT

The clinical development of fedratinib, a Janus kinase (JAK2) inhibitor, was terminated after reports of Wernicke's encephalopathy in myelofibrosis patients. Since Wernicke's encephalopathy is induced by thiamine deficiency, investigations were conducted to probe possible mechanisms through which fedratinib may lead to a thiamine-deficient state. In vitro studies indicate that fedratinib potently inhibits the carrier-mediated uptake and transcellular flux of thiamine in Caco-2 cells, suggesting that oral absorption of dietary thiamine is significantly compromised by fedratinib dosing. Transport studies with recombinant human thiamine transporters identified the individual human thiamine transporter (hTHTR2) that is inhibited by fedratinib. Inhibition of thiamine uptake appears unique to fedratinib and is not shared by marketed JAK inhibitors, and this observation is consistent with the known structure-activity relationship for the binding of thiamine to its transporters. The results from these studies provide a molecular basis for the development of Wernicke's encephalopathy upon fedratinib treatment and highlight the need to evaluate interactions of investigational drugs with nutrient transporters in addition to classic xenobiotic transporters.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Thiamine hydrochloride, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride solution, 5 M in H2O, BioReagent, for molecular biology, suitable for cell culture
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride solution, 5 M
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Thiamine hydrochloride, meets USP testing specifications
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Thiamine hydrochloride, reagent grade, ≥99% (HPLC)
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, tablet
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, for molecular biology, DNase, RNase, and protease, none detected, ≥99% (titration)
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride solution, 0.9% in water, BioXtra, suitable for cell culture
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, meets analytical specification of Ph. Eur., BP, USP, 99.0-100.5%
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥99%
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, BioXtra, ≥99.5% (AT)
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Thiamine hydrochloride, tested according to Ph. Eur.
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, BioUltra, for molecular biology, ≥99.5% (AT)
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride solution, BioUltra, for molecular biology, ~5 M in H2O
SKU
Pack Size
Availability
Price
Quantity
Supelco
Sodium chloride, reference material for titrimetry, certified by BAM, >99.5%
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, tested according to Ph. Eur.
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride solution, 0.85%
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Thiamine hydrochloride, ≥98%, FCC, FG
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, random crystals, optical grade, 99.9% trace metals basis
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride-35Cl, 99 atom % 35Cl
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, 99.999% trace metals basis
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, AnhydroBeads, −10 mesh, 99.999% trace metals basis
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium chloride, BioPerformance Certified, ≥99% (titration), suitable for insect cell culture, suitable for plant cell culture
SKU
Pack Size
Availability
Price
Quantity
Supelco
Thiamine hydrochloride, Pharmaceutical Secondary Standard; Certified Reference Material
SKU
Pack Size
Availability
Price
Quantity
SAFC
Sodium chloride solution, 5 M
SKU
Pack Size
Availability
Price
Quantity
USP
Thiamine hydrochloride, United States Pharmacopeia (USP) Reference Standard
SKU
Pack Size
Availability
Price
Quantity
Supelco
Thiamine Hydrochloride (B1), analytical standard
SKU
Pack Size
Availability
Price
Quantity
Thiamine hydrochloride, European Pharmacopoeia (EP) Reference Standard
SKU
Pack Size
Availability
Price
Quantity
Supelco
Sodium chloride, Pharmaceutical Secondary Standard; Certified Reference Material
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Potassium phosphate dibasic, ACS reagent, ≥98%
SKU
Pack Size
Availability
Price
Quantity