An exploratory study on pharmacogenetics of inosine-monophosphate dehydrogenase II in peripheral mononuclear cells from liver-transplant recipients (original) (raw)
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AIMS Long-term mycophenolate mofetil (MMF) therapy may induce inosine 5′-monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells (PBMCs), thus decreasing MMF immunosuppressive properties. Pharmacodynamic monitoring was used to investigate whether biological activity is altered after long-term therapy. METHODS IMPDH activity was measured in PBMC samples from 54 stable kidney transplant patients, already on MMF (for at least 3 months), before (t0) and 2 h after (t2) MMF morning dose administration; levels were monitored for up to 15 months, together with total mycophenolic acid (MPA) and free MPA concentrations. RESULTS During the 15 months’ monitoring, t0 IMPDH activity in transplant recipients increased from 5.9 3.7 nmol h-1 mg-1 [95% confidence interval (CI) 4.9, 6.9] to 9.0 3.9 nmol h-1 mg-1 (95% CI 7.2, 10.8), with an intra- and interpatient variability of 28% and 42%. Five patients experienced acute rejection during the follow-up: t0 IMPDH activity was increased during rejection vs. nonrejection, and the trend was significantly higher in rejecting than in nonrejecting subjects for the whole monitoring period. CONCLUSIONS Even though a correlation has been found between IMPDH activity and rejection, its efficacy as a predictive tool in long-term transplant outcomes may be affected by high interpatient variability; on the other hand, continuous monitoring of the IMPDH trend could make an effective prognostic parameter of rejection. Other trials also including pre-transplant data on both IMPDH expression and activity are warranted to better assess their role as biomarkers for MPA effect in clinical practice.
The Journal of Clinical Pharmacology, 2011
Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)-induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)-guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra-and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AU C0-12 h) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory E max model (EC 50 = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pre-transplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.
Expression of IMPDH mRNA after mycophenolate administration in male volunteers
BioMed research international, 2014
Mycophenolic acid (MPA) is the first-line antimetabolic immunosuppressants used in solid organ transplantation. Here, in vivo expressions of the pharmacodynamic marker IMPDH mRNA were analyzed to investigate its usefulness in assessing drug effects. Six healthy male volunteers who had the same genotype for genes known to be associated with drug metabolism and effects were selected to remove the confounding effect of these genotypes. Mycophenolate mofetil (MMF, 1 g) was administered once to each subject, and blood samples were collected with certain interval before and after MMF administration to measure lymphocyte expression levels of IMPDH1 and IMPDH2 mRNA. One week later, the experiment was repeated. Whereas IMPDH1 mRNA expression was stable, IMPDH2 mRNA expression showed 2 peaks in the first week. Both IMPDH1 and IMPDH2 mRNA expression in the second week remarkably decreased from the first week. The temporary increase in IMPDH2 mRNA expression in the first week might be due to a ...
Therapeutic Monitoring of Mycophenolate Mofetil in Organ Transplant Recipients
Clinical Pharmacokinetics, 2002
M ycophenolate mofetil (MMF) has become the single most used immunosuppressant in solid-organ transplantation. Despite a well-documented relationship and efficacy (in terms of acute rejection prophylaxis) and exposure to mycophenolic acids (MPA) as measured by area under the curve (AUC), excellent results have been achieved using a fixed-dosage regimen. In the past several years, there has been an increased interest in the utility of monitoring MPA concentrations to both increase efficacy and decrease toxicity, particularly in many current drug minimization protocols.
Transplantation, 2005
The addition of mycophenolate mofetil (MMF) to calcineurin inhibitor-based regimens reduces the incidence of acute rejection after kidney transplantation. The interpatient variability, changes over time of pharmacokinetic parameters, and the potential for drug interactions make the systemic exposure of mycophenolic acid (MPA) unpredictable at a fixed-dose regimen. An increase in plasma concentration of MPA significantly correlates with a decreased likelihood of an acute rejection after kidney or heart transplantation; therefore, a strategy of therapeutic drug monitoring for MMF therapy could improve outcome. Two large randomized, multicenter, prospective trials investigating the added value of therapeutic drug monitoring for MPA, by comparing fixed-dose treatment with concentration-controlled MMF treatment in kidney transplant recipients, are currently ongoing. More data are needed to fully establish the meaning of the reported prognostic value of preoperative inosine monophosphate dehydrogenase (IMPDH) activity, and longitudinal studies monitoring IMPDH activity after transplantation are eagerly awaited.
American Journal of Transplantation, 2004
Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase (IMPDH) activity, is usually administered as a standard dose of 1 g b.i.d. after renal transplantation. Because MMF dose reductions are associated with inferior outcome, we investigated pre-transplant IMPDH activity, MMF dose reductions and outcome. IMPDH activity was determined in isolated peripheral mononuclear cells immediately prior to renal transplantation. We observed considerable inter-individual variability in pre-transplant IMPDH activity (9.35 ± 4.22 nmol/mg/h). Thirty of 48 patients (62.5%) with standard MMF dose (1 g b.i.d.) had dose reductions within 3 years post-transplant; these patients also had significantly lower IMPDH activity. The area under the receiver-operating characteristics curve (AUC-ROC) for prediction of dose reduction within 6 months post-transplant was 0.75 (95% CI, 0.61-0.89; p < 0.004). IMPDH activity above the cutoff value, MMF dose reduction and age of recipient were significant contributors for the occurrence of acute rejection in the multivariate logistic regression. Patients with high IMPDH activity and MMF dose reduction had the highest rejection rate (81.8% vs. 36.4%; p < 0.01). Conclusion: Patients with low IMPDH activity experienced more complications of MMF therapy. High pre-transplant IMPDH activity and MMF dose reductions were associated with rejection. Determination of IMPDH activity prior to transplantation may help to improve MMF therapy after renal transplantation.
Clinical Biochemistry, 2001
The immunosuppressive activity of mycophenolate mofetil (MMF) is based on the reversible inhibition of inosine 5Јmonophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). It was the aim of this study to develop a nonradioactive method for specific measurement of IMPDH activity in isolated peripheral mononuclear cells (MNC). Methods: The procedure is based on the incubation of lysed MNC with inosine 5Ј-monophosphate (IMP) followed by direct chromatographic determination of produced xanthosine 5Ј-monophosphate (XMP). IMPDH activity was measured in MNC of MMF-treated patients and nontreated volunteers. Results: The within-run (n ϭ 10) and between-run (n ϭ 20) coefficients of variation (CV) for IMPDH activity were Ͻ 8% and Ͻ 10%, respectively. IMPDH activity in 60 healthy volunteers (19 -63 yr) ranged from 4.72 to 32.92 nmol/h/mg protein (mean ϭ 18.39 Ϯ 6.24). The IC 50 for in vitro inhibition of IMPDH activity was about 2 to 3 g/L. Application of a single dose of 1 g MMF in dialysis patients resulted in a significant inhibition (by 47-95%; p Ͻ 0.05) of IMPDH activity in lysed MNC. Conclusions: The proposed assay specifically and reliably measures IMPDH activity in MNC. The procedure is applicable to evaluate pharmacodynamic activity in MMF-treated patients. The observed interindividual variability of IMPDH activity may reflect pharmacodynamic differences in MMF-treated patients.