Abstract
Objective
UGT1A8 and UGT2B7 are important uridine diphosphate-glucuronosyltransferase isoforms for the glucuronidation of mycophenolic acid (MPA). The aim of this investigation was to elucidate MPA pharmacokinetics in UGT1A8 and UGT2B7 genotypes in Japanese renal transplant recipients.
Methods
Seventy-two recipients received repeated doses of mycophenolate mofetil and tacrolimus. On day 28 after renal transplantation, plasma MPA concentrations were measured for the next 24 h using high-performance liquid chromatography. UGT1A8*2 (A173G) and UGT2B7*2 (Y268) were detected using a PCR-RFLP-based procedure.
Results
There were no significant differences in daytime and nighttime pharmacokinetics of MPA between UGT1A8 or UGT2B7 genotypes. The mean daytime dose-adjusted AUC0–12 of MPA in UGT1A8*1/*1, *1/*2 and *2/*2 were 2.47, 2.33 and 2.57 ng·h/ml/mg/kg (P = 0.7711), and the mean nighttime AUC0–12 were 2.15, 2.00 and 2.08 ng·h/ml/mg/kg (P = 0.4656). The mean daytime and nighttime dose-adjusted AUC0–12 of MPA in UGT2B7*1/*1, *1/*2 and *2/*2 were 2.61, 2.24 and 2.03 ng·h/ml/mg/kg and 2.18, 1.94, and 1.45 ng·h/ml/mg/kg, respectively (P = 0.3475 and 0.2575). The mean nighttime Cmax, tmax, and AUC6–12/AUC0–12 ratio (enterohepatic circulation and recirculation ratio) of MPA in all UGT1A8 and UGT2B7 genotypes were lower, longer, and higher, respectively, than the daytime values.
Conclusions
Both UGT1A8 and UGT2B7 allelic variants seem not to affect Japanese interindividual variability for plasma MPA concentration. Regardless of UGT1A8 and UGT2B7 genetic polymorphisms, the absorption of MPA through enterohepatic recirculation is higher at night.
Similar content being viewed by others
References
Roth D, Colona J, Burke GW, Ciancio G, Esquenazi V, Miller J (1998) Primary immunosuppression with tacrolimus and mycophenolate mofetil for renal allograft recipients. Transplantation 27:248–252
Squifflet JP, Backman L, Claesson K, Dietl KH, Ekberg H, Forsythe JL, Kunzendorf U, Heemann U, Land W, Morales JM, Muhlbacher F, Talbot D, Taube D, Tyden G, van Hooff J, Schleibner S, Vanrenterghem Y (2001) European Tacrolimus-MMF Renal Study Group. Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients. Transplantation 15:63–69
Bullingham RE, Nicholls AJ, Kamm BR (1998) Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34:429-455
Shaw LM, Holt DW, Oellerich M, Meiser B, van Gelder T (2001) Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion. Ther Drug Monit 23:305–315
Guillemette C (2003) Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 3:136–158
Bernard O, Guillemette C (2004) The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants. Drug Metab Dispos 32:775-778
Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P (2005) Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos 33:139–146
Kuypers DR, Naesens M, Vermeire S, Vanrenterghem Y (2005) The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin Pharmacol Ther 78:351–361
Saeki M, Saito Y, Jinno H, Sai K, Ozawa S, Kurose K, Kaniwa N, Komamura K, Kotake T, Morishita H, Kamakura S, Kitakaze M, Tomoike H, Shirao K, Tamura T, Yamamoto N, Kunitoh H, Hamaguchi T, Yoshida T, Kubota K, Ohtsu A, Muto M, Minami H, Saijo N, Kamatani N, Sawada JI (2006) Haplotype structures of the UGT1A gene complex in a Japanese population. Pharmacogenomics J 6:63–75
Huang YH, Galijatovic A, Nguyen N, Geske D, Beaton D, Green J, Green M, Peters WH, Tukey RH (2002) Identification and functional characterization of UDP-glucuronosyltransferases UGT1A8*1, UGT1A8*2 and UGT1A8*3. Pharmacogenetics 12:287–297
Radominska-Pandya A, Little JM, Czernik PJ (2001) Human UDP-glucuronosyltransferase 2B7. Curr Drug Metab 2:283–298
Bhasker CR, McKinnon W, Stone A, Lo AC, Kubota T, Ishizaki T, Miners JO (2000) Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Pharmacogenetics 10:679–685
Holthe M, Klepstad P, Zahlsen K, Borchgrevink PC, Hagen L, Dale O, Kaasa S, Krokan HE, Skorpen F (2002) Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol 58:353–356
Sawyer MB, Innocenti F, Das S, Cheng C, Ramirez J, Pantle-Fisher FH, Wright C, Badner J, Pei D, Boyett JM, Cook E Jr, Ratain MJ (2003) A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 73:566–574
Kuypers DR, Vanrenterghem Y, Squifflet JP, Mourad M, Abramowicz D, Oellerich M, Armstrong V, Shipkova M, Daems J (2003) Twelve-month evaluation of the clinical pharmacokinetics of total and free mycophenolic acid and its glucuronide metabolites in renal allograft recipients on low dose tacrolimus in combination with mycophenolate mofetil. Ther Drug Monit 25:609–622
Shaw LM, Korecka M, Venkataramanan R, Goldberg L, Bloom R, Brayman KL (2003) Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 3:534–542
Kuypers DR, Claes K, Evenepoel P, Maes B, Coosemans W, Pirenne J, Vanrenterghem Y (2003) Long-term changes in mycophenolic acid exposure in combination with tacrolimus and corticosteroids are dose dependent and not reflected by trough plasma concentration: a prospective study in 100 de novo renal allograft recipients. J Clin Pharmacol 43:866–880
van der Logt EM, Bergevoet SM, Roelofs HM, van Hooijdonk Z, te Morsche RH, Wobbes T, de Kok JB, Nagengast FM, Peters WH (2004) Genetic polymorphisms in UDP-glucuronosyltransferases and glutathione S-transferases and colorectal cancer risk. Carcinogenesis 25:2407–2415
Lin GF, Guo WC, Chen JG, Qin YQ, Golka K, Xiang CQ, Ma QW, Lu DR, Shen JH (2005) An association of UDP-glucuronosyltransferase 2B7 C802T (His268Tyr) polymorphism with bladder cancer in benzidine-exposed workers in China. Toxicol Sci 85:502–506
Bernard O, Tojcic J, Journault K, Perusse L, Guillemette C (2006) Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid. Drug Metab Dispos 34:1539–1545
Holt DW (2002) Monitoring mycophenolic acid. Ann Clin Biochem 39:173–183
Mourad M, Wallemacq P, Konig J, de Frahan EH, Eddour DC, De Meyer M, Malaise J, Squifflet JP (2002) Therapeutic monitoring of mycophenolate mofetil in organ transplant recipients: is it necessary? Clin Pharmacokinet 41:319–327
Guengerich FP, Parikh A, Johnson EF, Richardson TH, von Wachenfeldt C, Cosme J, Jung F, Strassburg CP, Manns MP, Tukey RH, Pritchard M, Fournel-Gigleux S, Burchell B (1997) Heterologous expression of human drug-metabolizing enzymes. Drug Metab Dispos 25:1234–1241
Bhasker CR, McKinnon W, Stone A, Lo AC, Kubota T, Ishizaki T, Miners JO (2000) Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Pharmacogenetics 10:679–685
Shaw LM, Mick R, Nowak I, Korecka M, Brayman KL (1998) Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed graft function. J Clin Pharmacol 38:268–275
Basu NK, Kole L, Kubota S, Owens IS (2004) Human UDP-glucuronosyltransferases show atypical metabolism of mycophenolic acid and inhibition by curcumin. Drug Metab Dispos 32:768–773
Acknowledgements
This work was supported by a grant (No.18923015) from the Japan Society for the Promotion of Science, Tokyo, Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kagaya, H., Inoue, K., Miura, M. et al. Influence of UGT1A8 and UGT2B7 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 63, 279–288 (2007). https://doi.org/10.1007/s00228-006-0248-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-006-0248-2