@article {Hopkins8, author = {Ashley M. Hopkins and Mahin Moghaddami and David J. R. Foster and Susanna M. Proudman and Richard N. Upton and Michael D. Wiese}, title = {Intracellular CD3+ T Lymphocyte Teriflunomide Concentration Is Poorly Correlated with and Has Greater Variability Than Unbound Plasma Teriflunomide Concentration}, volume = {45}, number = {1}, pages = {8--16}, year = {2017}, doi = {10.1124/dmd.116.071985}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Leflunomide{\textquoteright}s active metabolite teriflunomide inhibits dihydro-oroate dehydrogenase, an enzyme essential to proliferation of T lymphocytes. As teriflunomide must reach the target site to have this effect, this study assessed the distribution of teriflunomide into T lymphocytes, as intracellular concentrations may be a superior response biomarker to plasma concentrations. CD3 MicroBeads (Miltenyi Biotec, Bergisch Gladbach, Germany) were used to extract CD3+ T cells from the peripheral blood of patients with rheumatoid arthritis who were taking a stable dose of leflunomide. Unbound plasma and intra-CD3+ T cell teriflunomide concentrations were quantified using liquid chromatography{\textendash}mass spectrometry. Concentration (log transformed) and partition differences were assessed through paired Student t tests. Sixteen patients provided plasma steady-state teriflunomide samples, and eight provided a sample 6{\textendash}12 weeks later. At time-point one, the geometric mean teriflunomide concentration (range) in CD3+ T cells was 18.12 μg/L (6.15{\textendash}42.26 μg/L) compared with 69.75 μg/L (32.89{\textendash}263.1 μg/L) unbound in plasma (P \< 0.001). The mean partition coefficient (range) for unbound plasma teriflunomide into CD3+ T cells was 0.295 (0.092{\textendash}0.632), which was significantly different from unity (P \< 0.001). The median (range) change in teriflunomide concentration between the two time points was 14\% (-10\% to 40\%) in unbound plasma and -29\% (-69 to 138\%) for CD3+ T cells. Because teriflunomide concentrations in CD3+ T cells were lower and displayed a higher intraindividual variability than the unbound plasma concentrations, its applicability as a therapeutic drug-monitoring marker may be limited.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/45/1/8}, eprint = {https://dmd.aspetjournals.org/content/45/1/8.full.pdf}, journal = {Drug Metabolism and Disposition} }