Pharmacodynamics of immunosuppression by mycophenolic acid: Inhibition of both lymphocyte proliferation and activation correlates with pharmacokinetics

Mechanisms of immunosuppressive action of mycophenolic acid (MPA) on rat ly mphocytes and correlations among MPA plasma concentrations (pharmacokinetic s) and its suppression of immune functions (pharmacodynamics) were studied in vitro and in vivo. In vitro, MPA inhibited concanavalin A-stimulated lym phocyte proliferation in blood [tritium-labeled thymidine ([H-3]TdR) incorp oration, percentage of lymphocytes positive for proliferating cell nuclear antigen, and in S-G(2)M by flow cytometry] and activation (percentage of ly mphocytes expressing CD25 or CD134). Maximum percent inhibitions (I-max) of lymphocyte functions and concentrations of MPA (mg/l in blood) inhibiting 50% of I-max (IC50) were 99%/0.14 mg/l for [H-3]TdR, 93%/0.28 mg/l for S-G( 2)M, 74%/0.29 mg/l for CD25, and 83%/0.24 mg/l for CD134. Blood sampled at different times after single or multiple oral MPA administrations at four d ose levels was assayed for lymphocyte functions and MPA plasma concentratio ns. I-max (%) and IC50 (mg/l in plasma by HPLC) were 98 to 99%/0.18 to 0.19 mg/l for [H-3]TdR, 88 to 98%/0.70 to 0.83 mg/l for S-G(2)M, 60 to 63%/0.65 to 0.81 mg/l for CD25, and 72 to 77%/0.61 to 0.74 mg/l for CD134. IC50 val ues for S-G(2)M, CD25, and CD134 were higher after multiple daily treatment s than after a single dose. There were clear and direct relationships among MPA dose levels, kinetics of MPA plasma concentrations, and dynamics of ly mphocyte functions. MPA treatment in vitro and in vivo inhibits not only mi togen-stimulated lymphocyte proliferation in whole blood but also lymphocyt e expression of cell surface cytokine receptors. These two different mechan isms of action may contribute to the therapeutic efficacy of MPA in vivo.