TY - JOUR T1 - Pharmacokinetics of oral and subcutaneous methotrexate in red and white blood cells in patients with early rheumatoid arthritis: the methotrexate monitoring trial JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 460 LP - 467 DO - 10.1136/ard-2022-223398 VL - 82 IS - 4 AU - Renske CF Hebing AU - Marry Lin AU - Maja Bulatovic Calasan AU - Ittai B Muller AU - Sohaila Mahmoud AU - Sandra Heil AU - Eduard A Struys AU - Bart JF van den Bemt AU - Jos WR Twisk AU - Willem Lems AU - Michael T Nurmohamed AU - Gerrit Jansen AU - Robert de Jonge Y1 - 2023/04/01 UR - http://ard.bmj.com/content/82/4/460.abstract N2 - Objective To investigate the pharmacokinetics of methotrexate polyglutamate (MTX-PG) accumulation in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) in patients with early rheumatoid arthritis (RA) after oral and subcutaneous MTX treatment.Methods In a clinical prospective cohort study (Methotrexate Monitoring study), newly diagnosed patients with RA were randomised for oral or subcutaneous MTX. At 1, 2, 3 and 6 months after therapy initiation, blood was collected and RBCs and PBMCs were isolated. MTX-PG1-6 concentrations were determined by mass spectrometry methods using stable isotopes of MTX-PG1-6 as internal standards.Results 43 patients (mean age: 58.5 years, 77% female) were included. PBMCs and RBCs revealed disparate pharmacokinetic profiles in both absolute MTX-PG accumulation levels and distribution profiles. Intracellular MTX-PG accumulation in PBMCs was significantly (p<0.001) 10-fold to 20-fold higher than RBCs at all time points, regardless of the administration route. MTX-PG distribution in PBMCs was composed of mostly MTX-PG1 (PG1>PG2>PG3). Remarkably, the distribution profile in PBMCs remained constant over 6 months. RBCs accumulated mainly MTX-PG1 and lower levels of MTX-PG2-5 at t=1 month. After 3 months, MTX-PG3 was the main PG-moiety in RBCs, a profile retained after 6 months of MTX therapy. Subcutaneous MTX administration results in higher RBC drug levels than after oral administration, especially shortly after treatment initiation.Conclusions This is the first study reporting disparate MTX-PG accumulation profiles in RBCs versus PBMCs in newly diagnosed patients with RA during 6 months oral or subcutaneous MTX administration. This analysis can contribute to improved MTX therapeutic drug monitoring for patients with RA.Trial registration number NTR 7149.Data are available on reasonable request. ER -