当前位置： SCI文献检索 > TRANSPLANTATION期刊下所有文献 > Pharmacodynamic assessment of mycophenolic acid-induced immunosuppression by measurement of inosine monophosphate dehydrogenase activity in a canine model.

Pharmacodynamic assessment of mycophenolic acid-induced immunosuppression by measurement of inosine monophosphate dehydrogenase activity in a canine model.

Abstract：

:The combination of pharmacokinetic and pharmacodynamic (measurement of the biological effect) monitoring of immunosuppressive drugs provides a method for the optimization of drug dosing. We chose to investigate this using mycophenolic acid (MPA), an immunosuppressive drug that mediates its effect by the inhibition of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines. Using an assay developed for measurement of IMPDH activity in whole blood, the concentration required for 50% inhibition of IMPDH activity was approximately 200 mg/L (58 +/- 8.3% for whole blood [n = 6] and 55 +/- 10.0% for isolated lymphocytes). To ascertain the relationship between MPA concentration and IMPDH inhibition in vivo, dogs were administered a single dose of mycophenolate mofetil, the pro-drug of MPA, at 20 or 40 mg/kg orally. Pharmacokinetic analysis revealed that the Cmax of the 40-mg/kg group was statistically greater than that of the 20-mg/kg group (P < 0.05). There were no statistical differences in the other parameters investigated (area under the curve, beta half-life, mean residence time, volume of distribution at steady state, and clearance) between the two treatment groups. The half-life was calculated at approximately 8 hr for both dose groups. There was also substantial variability among the dogs in the absorption and clearance of MPA. An inverse relationship was found between the MPA concentration and IMPDH. Maximal inhibition of IMPDH activity of 30-40% occurs approximately 2-4 hr after dosing, followed by a gradual restoration in enzyme activity. After 24 hr, there is an increase in IMPDH activity that exceeds the pre-dosing levels in some cases by 3-fold. Evaluation of the pharmacokinetic and the pharmacodynamic responses to MPA in the canine model suggests that the drug should be administered ever 8 hr to optimize its immunosuppressive efficacy. This combined approach can be used for optimization of doses of this and other immunosuppressive drugs.

journal_name

Transplantation

journal_title

Transplantation

authors

Langman LJ,Shapiro AM,Lakey JR,LeGatt DF,Kneteman NM,Yatscoff RW

doi

10.1097/00007890-199601150-00018

subject

Has Abstract

pub_date

1996-01-15 00:00:00

pages

87-92

issue

eissn

0041-1337

issn

1534-6080

journal_volume

pub_type

杂志文章

在线工具

Pharmacodynamic assessment of mycophenolic acid-induced immunosuppression by measurement of inosine monophosphate dehydrogenase activity in a canine model.