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 lymphocytes and correlations among MPA plasma concentrations (pharmacokinetics) and its suppression of immune functions (pharmacodynamics) were studied in vitro and in vivo. In vitro, MPA inhibited concanavalin A-stimulated lymphocyte proliferation in blood [tritium-labeled thymidine ([(3)H]TdR) incorporation, percentage of lymphocytes positive for proliferating cell nuclear antigen, and in S-G(2)M by flow cytometry] and activation (percentage of lymphocytes 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) (IC(50)) were 99%/0.14 mg/l for [(3)H]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 dose levels was assayed for lymphocyte functions and MPA plasma concentrations. I(max) (%) and IC(50) (mg/l in plasma by HPLC) were 98 to 99%/0.18 to 0.19 mg/l for [(3)H]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. IC(50) values for S-G(2)M, CD25, and CD134 were higher after multiple daily treatments than after a single dose. There were clear and direct relationships among MPA dose levels, kinetics of MPA plasma concentrations, and dynamics of lymphocyte functions. MPA treatment in vitro and in vivo inhibits not only mitogen-stimulated lymphocyte proliferation in whole blood but also lymphocyte expression of cell surface cytokine receptors. These two different mechanisms of action may contribute to the therapeutic efficacy of MPA in vivo.
Gummert
J F
JF
Transplantation Immunology, Department of Cardiothoracic Surgery, Stanford University Medical School, Stanford, California 94305-5407, USA.
Barten
M J
MJ
Sherwood
S W
SW
van Gelder
T
T
Morris
R E
RE
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D005434:Flow Cytometry; D006400:Hematocrit; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007958:Leukocyte Count; D008213:Lymphocyte Activation / Q000187:drug effects*; D018655:Lymphocyte Count / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D009173:Mycophenolic Acid / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis / Q000276:immunology
D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505718:Tnfrsf4 protein, rat; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D004247:DNA; D009173:Mycophenolic Acid