臨床泌尿器科68巻1号

2014年01月発行

綜説

タクロリムスの薬物動態・薬理遺伝学と個別投与量設計

著者： 佐藤滋¹ 三浦昌朋²

所属機関： ¹秋田大学医学部腎疾患先端医療センター ²秋田大学医学部附属病院薬剤部

ページ範囲：P.9 - P.18

文献概要

要旨　カルシニューリン阻害薬であるタクロリムスは，わが国で開発された免疫抑制薬であり，世界で広く使用されている最も強力なT細胞抑制薬である。しかし，腎毒性があり，その治療の適正血中濃度領域は狭い。タクロリムスの薬物動態は代謝酵素の遺伝子多型を含め，さまざまな因子によって影響を受ける。ここでは，筆者らの研究成果を中心に，腎移植におけるタクロリムスの薬物動態・薬理遺伝学を紹介する。さらに，遺伝子多型を基にしたタクロリムスの個別投与量設計についても，記載する。

参考文献

1）Barraclough KA, Isbel NM, Johnson DW, et al：Once-versus twice-daily tacrolimus：are the formulations truly equivalent? Drugs 71：1561-1577, 2011

2）Elens L, Hesselink DA, van Schaik, et al：Pharmacogenetics in kidney transplantation：recent updates and potential clinical applications. Mol Diag Ther 16：331-345, 2012

3）Hougardy JM, de Jonge H, Kuypers D, et al：The once-daily formulation of tacrolimus：a step forward in kidney transplantation? Transplantation 93：241-243, 2012

4）三浦昌朋，佐藤　滋：腎移植患者における免疫抑制剤の個別化療法．日病薬師会誌49：1061-1065，2013

5）Saeki T, Ueda K, Tanigawara Y, et al：Human P-glycoprotein transports cyclosporin A and FK506. J Biol Chem 268：6077-6080, 1993

6）Shiraga T, Matsuda H, Nagase K, et al：Metabolism of FK506, a potent immunosuppressive agent, by cytochrome P450 3A enzyme in rat, dog and human liver microsomes. Biochem Pharmacol 47：727-735, 1994

7）Hebert MF：Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev 27：201-214, 1997

8）Stevens JC：New Perspectives on the impact of cytochrome P450 3A expression for pediatric pharmacology. Drug Discov Today 11：440-445, 2006

9）Tsuchiya N, Satoh S, Tada H, et al：Influence of CYP3A5 and MDR1（ABCB1）polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation 78：1182-1187, 2004

10）Macphee IA, Fredericks S, Tai T, et al：Tacrolimus pharmacogenetics：polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement. Transplantation 74：1486-1489, 2002

11）Zheng H, Webber S, Zeevi A, et al：Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant 3：477-483, 2003

12）Hesselink DA, van Schaik RH, van der Heiden IP, et al：Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcinuerin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 74：245-254, 2003

13）Thervet E, Anglicheau D, King B, et al：Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 76：1233-1235, 2003

14）Zheng H, Zeevi A, Scuetz E, et al：Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. J Clin Pharmacol 44：135-140, 2004

15）Haufroid V, Mourad M, Van Kerckhove V, et al：The effect of CYP3A5 and MDR1（ABCB1）polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics 14：147-154, 2004

16）Goto M, Masuda S, Kiuchi T, et al：CYP3A5＊1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation. Pharmacogenetics 14：471-478, 2004

17）MacPhee IA, Fredericks S, Tai T, et al：The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant 4：914-919, 2004

18）Satoh S, Saito M, Inoue T, et al：CYP3A5＊1 allele associated with tacrolimus trough concentrations but not subclinical acute rejection or chronic allograft nephropathy in Japanese renal transplant recipients. Eur J Clin Pharmacol 65：473-481, 2009

19）Kuypers DR, de Jonge H, Naessens M, et al：CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxocity in renal recipients. Clin Pharmacol Ther 82：711-725, 2007

20）Miura Y, Satoh S, Saito M, et al：Factors increasing quantitative interstitial fibrosis from 0 hr to 1 year in living kidney transplant patients receiving tacrolimus. Transplantation 91：78-85, 2011

21）Hardinger KL, Park JM, Schnitzler MA, et al：Pharmacokinetics of tacrolimus in kidney transplant recipients：twice daily versus once daily dosing. Am J Transplant 4：621-625, 2004

22）Min DI, Chen HY, Lee MK, et al：Time-dependent disposition of tacrolimus and its effect on endo-thelin-1 in liver allograft recipients. Pharmacotherapy 17：457-463, 1997

23）Tada H, Satoh S, Iinuma M, et al：Chronopharmacokinetics of tacrolimus in kidney transplant recipients：occurrence of acute rejection. J Clin Pharmacol 43：859-865, 2003

24）Satoh S, Kagaya H, Saito M, et al：Lack of tacrolimus circadian pharmacokinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipients. Br J Clin Pharmacol 66：207-214, 2008

25）Bekersky I, Dressler D and Mekki Q：Effect of time of meal consumption on bioavailability of a single oral 5mg tacrolimus dose. J Clin Pharmacol 41：289-297, 2001

26）de Jonge H, Kuypers DR, Verbeke K, et al：Reduced C0 concentrations and increased dose requirements in renal allograft recipients converted to the novel once-daily tacrolimus formulation. Transplantation 90：523-529, 2010

27）Wu MJ, Cheng CY, Chen CH, et al：Lower variability of tacrolimus trough concentration after conversion from Prograf to Advagraf in stable kidney transplant recipients. Transplantation 92：648-652, 2011

28）Hougardy JM, Broeders N, Kianda M, et al：Conversion from Prograf to Advagraf among kidney transplant recipients results in sustained decrease in tacrolimus exposure. Transplantation 91：566-569, 2011

29）Niioka T, Satoh S, Kagaya H, et al：Comparison of pharmacokinetics and pharmacogenetics of once-and twice-daily tacrolimus in the early stage after renal transplantation. Transplantation 94：1013-1019, 2012

30）佐藤　滋，新岡丈典，加賀谷英彰，他：グラセプタのトラフ値はプログラフと同等か？―移植1年まで．日本臨床腎移植学会雑誌1：78-81，2013

31）MacPhee IA and Holt DW：A Pharmacogenetic strategy for immunosuppression based on the CYP3A5 genotype. Transplantation 85：163-165, 2008. 2008

32）Zhang J, Zhang X, Liu L, et al：Value of CYP3A5 genotyping on determining initial dosages of tacrolimus for Chinese renal transplant recipients. Transplant Proc 42：3459-3464, 2012

33）Thervet E, Loriot MA, Barbier S, et al：Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther 87：721-726, 2010