Pharmacodynamics of mycophenolic acid in heart allograft recipients: correlation of lymphocyte proliferation and activation with pharmacokinetics and graft histology.

Abstract:

BACKGROUND:Assays of drug blood levels are used for therapeutic immunosuppressive drug monitoring (pharmacokinetics, PK). We monitored lymphocyte functions (pharmacodynamics, PD) in allograft recipients treated with mycophenolic acid (MPA) to determine its mechanisms and the relationships among dose levels, PK, PD, and histological severity of graft rejection. METHODS:Lewis rats transplanted with Brown Norway (BN) rat hearts were treated with different dose levels of MPA for 8, 15, or 29 days at which times grafts were removed and scored for rejection grade. Blood was analyzed (high-performance liquid chromatography) for MPA plasma concentrations (area under the concentration-time curve0-24 hr, C6 hr, trough) and for lymphocyte functions using concanavalin A-stimulated whole blood assays to measure lymphocyte proliferation (tritium labeled thymidine incorporation and flow cytometric bivariate proliferating nuclear cell antigen/DNA analysis) and activation (percent lymphocytes expressing CD25 or CD134). PD values were AUE0-24 hr (area under the PD effect-time curve), maximum inhibition and trough. RESULTS:MPA equipotently suppressed (by flow cytometry) both proliferation and activation and these effects correlated with MPA plasma levels (r2=0.80-0.91). Relationships among MPA dose levels, PK and PD were clear, direct, and reproducible. Correlation coefficients after 8 days of MPA treatment were: 0.90, 0.87, and 0.49 for MPA PK (AUC0-24 hr, C6 hr and trough) versus rejection scores; 0.80-0.89, 0.86-0.92, and 0.25-0.52 for PD flow cytometric assays (AUE0-24 hr, maximum inhibition, and trough) versus rejection scores. CONCLUSIONS:MPA inhibits both lymphocyte proliferation and activation. PD by flow cytometry (FCM) correlates highly with severity of graft rejection, showing that PD of MPA measured in peripheral blood predicts immune cell activity in graft tissue.

journal_name

Transplantation

journal_title

Transplantation

authors

Gummert JF,Barten MJ,van Gelder T,Billingham ME,Morris RE

doi

10.1097/00007890-200010150-00009

subject

Has Abstract

pub_date

2000-10-15 00:00:00

pages

1038-49

issue

7

eissn

0041-1337

issn

1534-6080

journal_volume

70

pub_type

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