Interactions of janus kinase inhibitors with drug transporters and consequences for pharmacokinetics and toxicity.

Abstract

Introduction: Janus kinase inhibitors (JAKinibs) constitute an emerging and promising pharmacological class of anti-inflammatory or anti-cancer drugs, used notably for the treatment of rheumatoid arthritis and some myeloproliferative neoplasms.Areas covered: This review provides an overview of the interactions between marketed JAKinibs and major uptake and efflux drug transporters. Consequences regarding pharmacokinetics, drug-drug interactions and toxicity are summarized.Expert opinion: JAKinibs interact in vitro with transporters in various ways, as inhibitors or as substrates of transporters or as regulators of transporter expression. This may theoretically result in drug-drug interactions (DDIs), with JAKinibs acting as perpetrators or as victims, or in toxicity, via impairment of thiamine transport. Clinical significance in terms of DDIs for JAKinib-transporter interactions remains however poorly documented. In this context, the in vivo unbound concentration of JAKinibs is likely a key parameter to consider for evaluating the clinical relevance of JAKinibs-mediated transporter inhibition. Additionally, the interplay with drug metabolism as well as possible interactions with transporters of emerging importance and time-dependent inhibition have to be taken into account. The role drug transporters may play in controlling cellular JAKinib concentrations and efficacy in target cells is also an issue of interest.

• Authors: Karima Alim, Arnaud Bruyère, Alain Lescoat, Elodie Jouan, Valérie Lecureur, Marc Le Vée, Olivier Fardel
• Journal: Expert opinion on drug metabolism & toxicology (Expert Opin Drug Metab Toxicol) Vol. 17 Issue 3 Pg. 259-271 (Mar 2021) ISSN: 1744-7607 [Electronic] England
• PMID: 33292029 (Publication Type: Journal Article, Review)

Chemical References

• Janus Kinase Inhibitors
• Membrane Transport Proteins
• Pharmaceutical Preparations
• Thiamine

Topics

• Animals
• Biological Transport (drug effects)
• Drug Interactions
• Humans
• Janus Kinase Inhibitors (pharmacology)
• Membrane Transport Proteins (metabolism)
• Pharmaceutical Preparations (metabolism)
• Pharmacokinetics
• Thiamine (metabolism)
• Time Factors