Evaluation of inosin-5'-monophosphate dehydrogenase activity during maintenance therapy with tacrolimus.
OBJECTIVE
The aim of this study was to identify a target range for inosin-5'-monophosphate dehydrogenase (IMPDH) activity in maintenance therapy with tacrolimus (TCL), and to apply the measurement of IMPDH activity to the therapeutic drug monitoring for mycophenolate mofetil (MMF).


METHODS
Eleven patients with renal transplants and 10 healthy volunteers were investigated. All patients were treated with a combination of TCL, steroid and MMF for 2 months after transplantation, and were in stable and good condition. IMPDH activity was determined indirectly by measuring xanthosine 5'-monophophate in cell lysates supplemented with IMP and beta-nicotine adenine dinucleotide using an high-performance liquid chromatography (HPLC) method.


RESULTS
The within-run reproducibility of the assay was excellent, with relative standard deviation (RSD) values of 0.41-4.08%. The mean differences between the spiked concentrations of xanthosine 5'-monophophate and their real values (mean relative errors; MREs) were within a range of 2.66-8.89%, showing good accuracy. The interday RSD values were 1.51-6.12% and MREs ranged from 2.10% to 8.89%. Cell lysates showed a 5-6 nmol/L IC(50) mycophenolic acid (MPA) concentration. TCL, cyclosporine and prednisolone did not affect IMPDH activity. The peak MPA concentration was achieved at 1 h after dosing. IMPDH activity decreased to 75% and 67% at 1 and 2 h after dosing respectively. Therefore, the inhibition rates of MPA against IMPDH activity may be adequate at 25-40% in TCL maintenance therapy.


CONCLUSIONS
Inosin-5'-monophosphate dehydrogenase activity in cell lysates could be reliably determined by HPLC. A 25-40% inhibition of IMPDH activity may be an appropriate range for preventing rejection with MPF but this requires further validation using larger studies with harder outcomes such as rejection episodes.
Maiguma
T
T
Department of Clinical Pharmacy, School of Pharmacy, Shujitsu University, Okayama, Japan.
Yosida
T
T
Otsubo
K
K
Okabe
Y
Y
Sugitani
A
A
Tanaka
M
M
Oishi
R
R
Teshima
D
D
D000328:Adult; D054316:Biomarkers, Pharmacological / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000097:blood*; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015203:Reproducibility of Results; D012265:Ribonucleotides / Q000032:analysis; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019820:Xanthine; D055815:Young Adult
D054316:Biomarkers, Pharmacological; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011355:Prodrugs; D012265:Ribonucleotides; D019820:Xanthine; C011141:xanthosine monophosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D016559:Tacrolimus