Abstract
Leflunomide is a prodrug that is metabolized to the active metabolite, teriflunomide (A77 1726), to inhibit the enzyme dihydroorotate dehydrogenase and decrease the synthesis of pyrimidine nucleotides for DNA and RNA synthesis. Teriflunomide is primarily used for the treatment of rheumatoid arthritis and multiple sclerosis.
A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify the drug teriflunomide over a concentration range of 5 ng/mL–200 μg/mL in serum or plasma. The calibration curve was divided into two separate overlapping regions of the analytical measurement range, with a high curve and a low curve range. Samples are first analyzed using the high-range calibration curve after a 100-fold dilution of the sample extract. Samples falling below the upper curve region are evaluated again without dilution and quantified, if possible, against the low curve calibration standards. This method can be used to support therapeutic drug monitoring of patients that are administered with leflunomide therapy.
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References
Schattenkirchner M (2000) The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review. Immunopharmacology 47:291–298
Oh J, O’ Connor PW (2013) Teriflunomide for the treatment of multiple sclerosis. Semin Neurol 33:45–55
Chacko B, John GT (2012) Leflunomide for cytomegalovirus: bench to bedside. Transplant Infect Dis 14:111–120
Teschner S, Gerke P, Geyer M, Wilpert J, Krumme B, Benzing T, Walz G (2009) Leflunomide therapy for polyomavirus-induced allograft nephropathy: efficient BK virus elimination without increased risk of rejection. Transplant Proc 41:2533–2538
Babic-Naglic D, Anic B, Novak S, Grazio S, Martinavic Kaliterna D (2010) Treatment of rheumatoid and psoriatic arthritis−review of leflunomide. Reumatizam 57:161–162
Pinto P, Dougados M (2006) Leflunomide in clinical practice. Acta Reumatol Portuguesa 31:215–224
Prakash A, Jarvis B (1999) Leflunomide: a review of its use in active rheumatoid arthritis. Drugs 58:1137–1164
Breedveld FC, Dayer JM (2000) Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis 59:841–849
Schmidt A, Schwind B, Gillich M, Brune K, Hinz B (2003) Simultaneous determination of leflunomide and its active metabolite, A77 1726, in human plasma by high-performance liquid chromatography. Biomed Chromatogr 17:276–281
Mutlu D, Saglik I, Koyun M, Comak E, Mutlu E, Uslu Gokceoglu A, Cagla Dogan S, Dinckan A, Akbas SH, Akkaya B, Akman S, Suleymanlar G, Colak D (2013) BK virus infections in pediatric kidney transplant recipients. Mikrobiyol Bul 47:461–471
Huttemann M, Shipkova M, Klett C, Hasche G, Wilhelm J, Bolley R, Olbricht C, Wieland E (2013) Total and free plasma concentrations of the active metabolite of leflunomide in relation to therapeutic outcome in kidney transplant recipients with BK-virus nephropathy. Transplant Proc 45:1611–1613
Brent RL (2001) Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child. Teratology 63:106–112
Chan V, Charles BG, Tett SE (2004) Rapid determination of the active leflunomide metabolite A77 1726 in human plasma by high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life 803:331–335
van Roon EN, Yska JP, Raemaekers J, Jansen TL, van Wanrooy M, Brouwers JR (2004) A rapid and simple determination of A77 1726 in human serum by high-performance liquid chromatography and its application for optimization of leflunomide therapy. J Pharm Biomed Anal 36:17–22
Parekh JM, Vaghela RN, Sutariya DK, Sanyal M, Yadav M, Shrivastav PS (2010) Chromatographic separation and sensitive determination of teriflunomide, an active metabolite of leflunomide in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 878:2217–2225
Rule GS, Clark ZD, Yue B, Rockwood AL (2013) Correction for isotopic interferences between analyte and internal standard in quantitative mass spectrometry by a nonlinear calibration function. Anal Chem 85:3879–3885
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The authors would like to thank the ARUP Institute for Clinical and Experimental Pathology for making this work possible.
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Rule, G.S., Rockwood, A.L., Johnson-Davis, K.L. (2019). LC-MS/MS Method for the Quantification of the Leflunomide Metabolite, Teriflunomide, in Human Serum/Plasma. In: Langman, L., Snozek, C. (eds) LC-MS in Drug Analysis. Methods in Molecular Biology, vol 1872. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8823-5_8
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DOI: https://doi.org/10.1007/978-1-4939-8823-5_8
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