title: Mycophenolic acid exposure and complement fraction C3 influence inosine 5'-monophosphate dehydrogenase activity in systemic lupus erythematosus.
abstract: Background Mycophenolate mofetil has recently been reported to be effective against systemic lupus erythematosus. The influence of the pharmacokinetics of mycophenolic acid, the active form of mycophenolate mofetil and the major inactive mycophenolic acid phenolic glucuronide on the activity of the target enzyme inosine 5'-monophosphate dehydrogenase, is expected to be revealed. The aim of this study was to identify the factors associated with inosine 5'-monophosphate dehydrogenase activity in systemic lupus erythematosus patients. Methods Fifty systemic lupus erythematosus patients in remission maintenance phase (29 received mycophenolate mofetil [MMF+] and 21 did not [MMF-]) were enrolled. Median and interquartile range of dose of mycophenolate mofetil were 1500 and 1000-1500 mg/day, respectively. Stepwise multiple linear regression analysis was performed to assess the dependence between inosine 5'-monophosphate dehydrogenase activity and 25 predictor values including predose plasma concentrations of free mycophenolic acid and mycophenolic acid phenolic glucuronide. Results Median and interquartile range of predose total plasma concentrations of mycophenolic acid and mycophenolic acid phenolic glucuronide were 2.73 and 1.43-5.73 and 25.5 and 13.1-54.7  µg/mL, respectively. Predose inosine 5'-monophosphate dehydrogenase activity was significantly higher in MMF+ than MMF- patients (median 38.3 and 20.6 nmoL xanthosine 5'-monophosphate/g haemoglobin/h, P<0.01). The plasma concentration of free mycophenolic acid phenolic glucuronide, complement fraction C3 and body weight were significant predictors accounting for interindividual variability in the inosine 5'-monophosphate dehydrogenase activity (adjusted R2= 0.52, P < 0.01) in a multivariate analysis. Conclusions Predose inosine 5'-monophosphate dehydrogenase activity was higher in systemic lupus erythematosus patients receiving mycophenolate mofetil therapy. Inosine 5'-monophosphate dehydrogenase activity may be determined by mycophenolic acid exposure and complement fraction C3 in systemic lupus erythematosus patients.
authors.affiliation: 1 Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Mino
authors.affiliation: 1 Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Naito
authors.affiliation: 2 Department of Rheumatology, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Shimoyama
authors.affiliation: 2 Department of Rheumatology, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Ogawa
authors.affiliation: 1 Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kawakami
mesh_terms: D000328:Adult; D001835:Body Weight; D003176:Complement C3 / Q000378:metabolism*; D003430:Cross-Sectional Studies; D004334:Drug Administration Schedule; D005260:Female; D020719:Glucuronides / Q000097:blood* / Q000493:pharmacokinetics; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000097:blood*; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012074:Remission Induction; D012265:Ribonucleotides / Q000097:blood; D019820:Xanthine
chemical_list: C038245:C3 protein, human; D003176:Complement C3; D020719:Glucuronides; D007166:Immunosuppressive Agents; D012265:Ribonucleotides; D019820:Xanthine; C011141:xanthosine monophosphate; C113145:mycophenolic acid glucuronide; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid
keywords: Clinical studies; pharmacokinetics