Determining the effect of CYP2C9 genotypes on diclofenac metabolism using individualized coupled physiology-based pharmacokinetic modeling
Edginton, A.N.(1), S. Willmann (1), Sevestre, M (2), Kirchheiner, J (3)
(1) Competence Center Systems Biology, Bayer Technology Services GmbH, 51368 Leverkusen, Germany; (2) Competence Center Computational Solutions, Bayer Technology Services GmbH, 51368 Leverkusen, Germany; (3) Department of Pharmacology of Natural Products & Clinical Pharmacology, University of Ulm, D-89081Ulm, Germany.
Objective: To determine the extent of diclofenac clearance due to hydroxylation to 4’-hydroxydiclofenac in 20 adults genotyped as CYP2C9 amino acid variants using individualized, coupled, physiology-based pharmacokinetic (PBPK) models.
Methods: In vivo experimental plasma concentration time curves for diclofenac and its CYP2C9-mediated metabolite, 4-OH diclofenac, were taken from Kirchheiner et al . Plasma concentration time curves for each individual were simulated using the physiology-based pharmacokinetic software, PK-Sim® (Bayer Technology Services GmbH,
The intrinsic clearance of diclofenac mediated by CYP2C9 was determined in each individual and compared to the individual CYP2C9 genotype.
Results: Clearance of diclofenac due to CYP2C9 metabolism was low with, on average, less than 25 % being due to the production of 4-OH diclofenac. In comparison to the wildtype, CYP2C9*1, individuals homozygous for the less active variant CYP2C9*3 showed lower intrinsic clearance. There was no clear trend for individuals carrying either the CYP2C9*2 allele or for individuals heterozygous for CYP2C9*3.
Conclusion: Due to the low clearance of diclofenac through the CYP2C9 pathway, total clearance is not affected by genotype; a finding in accordance with clinical studies but not with in vitro data showing that CYP2C9 serves as a major elimination pathway. The use of individualized coupled PBPK models allows for a separation of clearance pathways for an assessment of genotype effects.
 Kirchheiner J, Ingolf M, Steinbach N et al. 2003. Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans. Br J Clin Pharmacol 55: 51-61.