2020
DOI: 10.3390/ijms21186632
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Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA

Abstract: Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease in which synovial fibroblasts (SF) play a key role. Baricitinib and Tofacitinib both act intracellularly, blocking the ATP-binding side of JAK proteins and thereby the downstream signalling pathway via STAT-3. Therefore, we investigated the role of organic cation transporters (OCTs) in Baricitinib and Tofacitinib cellular transport. Methods: OCT expression was analysed in SF isolated from RA and osteoarthritis (OA) patients, as well as peri… Show more

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Cited by 17 publications
(9 citation statements)
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“…Noteworthy, baricitinib uptake by different tissues does not depend on organic cation transporters. There are significant differences between the two JAK inhibitors (also considered tyrosine kinase inhibitors) [ 70 ]. Ruxolitinib is metabolized by CYP3A4 and CYP2C19, whereas baricitinib metabolisms is CYP-independent, and the drug is excreted unchanged in the urine.…”
Section: Discussionmentioning
confidence: 99%
“…Noteworthy, baricitinib uptake by different tissues does not depend on organic cation transporters. There are significant differences between the two JAK inhibitors (also considered tyrosine kinase inhibitors) [ 70 ]. Ruxolitinib is metabolized by CYP3A4 and CYP2C19, whereas baricitinib metabolisms is CYP-independent, and the drug is excreted unchanged in the urine.…”
Section: Discussionmentioning
confidence: 99%
“…The CL R of tofacitinib was significantly slower in the presence of voriconazole after either intravenous or oral co-administration of both drugs, which is attributable to the significantly greater AUC of tofacitinib, due to the slower hepatic and intestinal metabolism of tofacitinib in both routes of administration ( Table 1 ). Tofacitinib is mainly excreted in urine via an organic cation transporter [ 41 ]; however, the Ae 0–24 h values of tofacitinib were comparable in the absence and presence of voriconazole for both intravenous and oral routes, indicating that voriconazole does not inhibit the organic cation transporter for the excretion of tofacitinib. Therefore, the slower CL R of tofacitinib when co-administered with voriconazole is attributable to the greater AUC of tofacitinib, in turn due to the metabolic inhibition of tofacitinib caused by voriconazole.…”
Section: Discussionmentioning
confidence: 99%
“…A different study found MATE1 to be increased in OA as opposed to RA. MATE1 was also determined to mediate transport of Tofacitinib, a blocker of the ATP-binding side of Janus kinase (JAK) proteins and tyrosine kinase inhibitor, from RA FLS ( 68 ). The increased expression of MATE1 in OA allows tofacitinib to be exported out of the cell, while the lower activity of MATE1 in RA does not allow tofacitinib to leave the cell, thus allowing tofacitinib to undergo its intended effects.…”
Section: Slc47 Multidrug and Toxin Extrusion Familymentioning
confidence: 99%