title: Nonsteroidal anti-inflammatory drugs may reduce enterohepatic recirculation of mycophenolic acid in patients with childhood-onset systemic lupus erythematosus.
abstract: BACKGROUND
  The large interindividual differences observed in mycophenolic acid (MPA) pharmacokinetics (MPA-PK) are in part attributed to the large variability in enterohepatic recirculation (EHC) of the drug. The main metabolite of MPA, MPA glucuronide is actively secreted into the bile via the multidrug resistance-associated protein 2 (MRP2) transporter. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the MRP2 transporter, which can alter EHC and drug exposure. Here, we evaluated the effects of this potential drug-transporter interaction on MPA-PK in a cohort of patients with childhood-onset systemic lupus erythematosus on mycophenolate mofetil therapy.
  
  
  METHODS
  Full MPA concentration-time profiles and demographics including comedications were available for 19 patients with childhood-onset systemic lupus erythematosus. Concentrations at predose (C(trough)), 9 hour (C₉), and nadir (C(nadir); defined as the lowest concentration between C(max) and C₉), and area under the curve (AUC₀₋₁₂ and AUC₆₋₁₂) were assessed using standard methods (WinNonlin5.1). AUC6-12/AUC₀₋₁₂ and C₉/C(nadir) ratios were used to evaluate the effects of NSAID treatment on MPA-PK.
  
  
  RESULTS
  Eleven out of 19 patients were on NSAID treatment and did not show visual evidence of EHC in their PK profile. In contrast, patients not on NSAID therapy showed evidence of EHC-related MPA concentration increase in the later part of their PK profiles, typically after 6 hours. This phenomenon could be well characterized by the C₉/C(nadir) ratio, which was significantly lower in the NSAID-treated cohort (P < 0.01).
  
  
  CONCLUSIONS
  These preliminary data suggest that the concomitant intake of NSAIDs may lower EHC of MPA possibly through the inhibition of MRP2 transport of MPA-G. Further mechanism-based studies are needed to further elucidate this potential transporter interaction.
authors.affiliation: Division of Clinical Pharmacology and Pediatric Pharmacology Research Unit, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. tsuyoshi.fukuda@cchmc.org
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.forename: Hermine I
authors.initials: HI
authors.lastname: Brunner
authors.forename: Anna Carmela P
authors.initials: AC
authors.lastname: Sagcal-Gironella
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D004764:Enterohepatic Circulation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000145:classification* / Q000188:drug therapy*; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009173:Mycophenolic Acid / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; C000715087:ABCC2 protein, human