他克莫司、环孢素与三唑类抗真菌药的代谢及药物相互作用
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摘要
他克莫司和环孢素是广泛用于器官移植领域和自身免疫系统疾病治疗的钙调磷酸酶抑制剂,主要经细胞色素P450(CYP450)代谢,其中CYP3A5基因多态性对他克莫司代谢有显著影响。免疫抑制剂的使用是真菌感染的危险因素,目前三唑类抗真菌药作为广谱抗真菌药在临床上使用广泛。各个三唑类抗真菌药的代谢途径有所差异,其中伏立康唑的代谢受CYP2C19基因多态性影响大。他克莫司、环孢素与三唑类抗真菌药联用时可能发生药物相互作用。本文就他克莫司、环孢素与三唑类抗真菌药的代谢及其药物相互作用做一综述,以期为临床应用提供参考。
Tacrolimus and cyclosporine are calcineurin inhibitors widely used in organ transplantation and autoimmune diseases,both of them mainly metabolized by cytochrome P450(CYP450),and the gene polymorphism of CYP3 A5 has a significant effect on tacrolimus metabolism.The usage of immunosuppressive agents is a risk factor for fungal infection,and triazole antifungals are widely used as broad-spectrum antifungal drugs in clinical practice.The metabolic pathway of each triazole antifungal is different,and the metabolism of voriconazole is greatly affected by the gene polymorphism of CYP2 C19.Administration of tacrolimus,cyclosporine and triazole antifungals may results in a drug-drug interaction(DDI).This review summarizes the metabolism and DDI of tacrolimus,cyclosporine and triazole antifungals in order to provide reference for clinical application.
Tacrolimus and cyclosporine are calcineurin inhibitors widely used in organ transplantation and autoimmune diseases,both of them mainly metabolized by cytochrome P450(CYP450),and the gene polymorphism of CYP3 A5 has a significant effect on tacrolimus metabolism.The usage of immunosuppressive agents is a risk factor for fungal infection,and triazole antifungals are widely used as broad-spectrum antifungal drugs in clinical practice.The metabolic pathway of each triazole antifungal is different,and the metabolism of voriconazole is greatly affected by the gene polymorphism of CYP2 C19.Administration of tacrolimus,cyclosporine and triazole antifungals may results in a drug-drug interaction(DDI).This review summarizes the metabolism and DDI of tacrolimus,cyclosporine and triazole antifungals in order to provide reference for clinical application.
引文
1 Vella JP,Sayegh MH.Maintenance pharmacological immunosuppressive strategies in renal transplantation.Postgrad med J,1997,73(861):386-390.
2 Khwaja A.KDIGO Guidelines for Care of the Kidney Transplant Recipient.Nephron Clin Pract,2010,116(1):c27-c28.
3 中国医师协会器官移植医师分会.中国肾移植受者免疫抑制治疗指南(2016版).器官移植,2016,7(5):327-331.
4 Dai Y,Iwanaga K,Lin YS,et al.In vitro metabolism of cyclosporine A by human kidney CYP3A5.Biochemical Pharmacology,2004,68(9):1889-1902.
5 Dai Y,Hebert MF,Isoherranen N,et al.Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro.Drug Metab Dispos,2006,34(5):836-847.
6 Pappas PG,Alexander BD,Andes DR,et al.Invasive Fungal Infections among Organ Transplant Recipients:Results of the Transplant‐Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis,2010,50(8):1101-1111.
7 Davis S,Gralla J,Klem P,et al.Lower tacrolimus exposure and time in therapeutic range increase the risk of de novo donor-specific antibodies in the first year of kidney transplantation.Am J Transplant,2018,18(4):907-915.
8 张鑫,刘志红,郑敬民,等.肾移植患者他克莫司血药浓度的影响因素.肾脏病与透析肾移植杂志,2005,14(4):333-338.
9 朱琳,常水,曲振华,等.CYP3A4、CYP3A5和MDR1基因多态性与肾移植受者他克莫司血药浓度的关系.肾脏病与透析肾移植杂志,2017,26(6):522-527.
10 Riegersperger M,Plischke M,Steinhauser C,et al.The Effect of ABCB1 Polymorphisms on Serial Tacrolimus Concentrations in Stable Austrian Long-Term Kidney Transplant Recipients.Clin Lab,2016,62(10):1965-1972.
11 Chen P,Li J,Li J,et al.Dynamic effects of CYP3A5 polymorphism on dose requirement and trough concentration of tacrolimus in renal transplant recipients.J Clin Pharm Ther,2017,42(1):93-97.
12 Birdwell KA,Decker B,Barbarino JM,et al.Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing.Clin Pharmacol Ther,2015,98(1):19-24.
13 方洁,陈冰,张伟霞,等.肾移植中环孢素的血药浓度与多药耐药基因多态性的关系.中国临床药学杂志,2008,17(5):265-269.
14 Staatz CE,Goodman LK,Tett SE.Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the p￣h￣a￣r￣m￣a￣c￣o￣k￣i￣n￣e￣t￣i￣c￣s and p￣h￣a￣r￣m￣a￣c￣o￣d￣y￣n￣a￣m￣i￣c￣s of calcineurin inhibitors:Part I.Clin Pharmacokinet,2010,49(3):141-175.
15 杜迪,李维亮,辛华雯.环孢素A的药物基因组学研究进展.中国药师,2018,21(04):695-700.
16 Tang HL,Ma LL,Xie HG,et al.Effects of the CYP3A5*3 variant on cyclosporine exposure and acute rejection rate in renal transplant patients:a meta-analysis.Pharmacogenet Genomics,2010,20(9):525-531.
17 Patterson TF,Thompson GR,Denning DW,et al.Practice Guidelines for the Diagnosis and Management of Aspergillosis:2016 Update by the Infectious Diseases Society of America.Clin Infect Dis,2016,63(4):e1-e60.
18 Pappas PG,Kauffman CA,Andes DR,et al.Clinical Practice Guideline for the Management of Candidiasis:2016 Update by the Infectious Diseases Society of America.Clin Infect Dis,2016,62(4):e1-50.
19 Hyland R,Jones BC,Smith DA.Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole.Drug Metab Dispos,2003,31(5):540-547.
20 Moriyama B,Obeng AO,Barbarino J,et al.Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy.Clin Pharmacol Ther,2017,102(1):45-51.
21 曲洪澜,郭丹丹,徐婷,等.CYP2C19基因多态性对血液病患者伏立康唑血药浓度的影响及血药浓度监测在侵袭性真菌病防治中的价值.中华血液学杂志,2018,39(3):202-206.
22 Ashbee HR,Barnes RA,Johnson EM,et al.Therapeutic drug monitoring (TDM) of antifungal agents:guidelines from the British Society for Medical Mycology.J Antimicrob Chemother,2014,69(5):1162-1176.
23 Lestner J,Hope WW.Itraconazole:an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections.Expert Opin Drug Metab Toxicol,2013,9(7):911-926.
24 Brammer KW,Farrow PR,Faulkner JK.Pharmacokinetics and tissue penetration of fluconazole in humans.Rev Infect Dis,1990,12 Suppl 3:S318-326.
25 Brüggemann RJ,Alffenaar JW,Blijlevens NM,et al.Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents.Clin Infect Dis,2009,48(10):1441-1458.
26 Vanhove T,Bouwsma H,Hilbrands L,et al.Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients.Am J Transplant,2017,17(9):2372-2380.
27 Groll AH,Townsend R,Desai A,et al.Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4.Transpl Infect Dis,2017,19(5).
28 Zhang S,Pillai VC,Mada SR,et al.Effect of voriconazole and other azole antifungal agents on CYP3A activity and metabolism of tacrolimus in human liver microsomes.Xenobiotica,2012,42(5):409-416.
29 Imamura CK,Furihata K,Okamoto S,et al.Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole.J Clin Pharmacol,2016,56(4):408-413.
30 Iwamoto T,Monma F,Fujieda A,et al.Effect of Genetic Polymorphism of CYP3A5 and CYP2C19 and Concomitant Use of Voriconazole on Blood Tacrolimus Concentration in Patients Receiving Hematopoietic Stem Cell Transplantation.Ther Drug Monit,2015,37(5):581-588.
31 Lempers VJ,Martial LC,Schreuder MF,et al.Drug-interactions of azole antifungals with selected immunosuppressants in transplant patients:strategies for optimal management in clinical practice.Curr Opin Pharmacol,2015,24:38-44.
2 Khwaja A.KDIGO Guidelines for Care of the Kidney Transplant Recipient.Nephron Clin Pract,2010,116(1):c27-c28.
3 中国医师协会器官移植医师分会.中国肾移植受者免疫抑制治疗指南(2016版).器官移植,2016,7(5):327-331.
4 Dai Y,Iwanaga K,Lin YS,et al.In vitro metabolism of cyclosporine A by human kidney CYP3A5.Biochemical Pharmacology,2004,68(9):1889-1902.
5 Dai Y,Hebert MF,Isoherranen N,et al.Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro.Drug Metab Dispos,2006,34(5):836-847.
6 Pappas PG,Alexander BD,Andes DR,et al.Invasive Fungal Infections among Organ Transplant Recipients:Results of the Transplant‐Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis,2010,50(8):1101-1111.
7 Davis S,Gralla J,Klem P,et al.Lower tacrolimus exposure and time in therapeutic range increase the risk of de novo donor-specific antibodies in the first year of kidney transplantation.Am J Transplant,2018,18(4):907-915.
8 张鑫,刘志红,郑敬民,等.肾移植患者他克莫司血药浓度的影响因素.肾脏病与透析肾移植杂志,2005,14(4):333-338.
9 朱琳,常水,曲振华,等.CYP3A4、CYP3A5和MDR1基因多态性与肾移植受者他克莫司血药浓度的关系.肾脏病与透析肾移植杂志,2017,26(6):522-527.
10 Riegersperger M,Plischke M,Steinhauser C,et al.The Effect of ABCB1 Polymorphisms on Serial Tacrolimus Concentrations in Stable Austrian Long-Term Kidney Transplant Recipients.Clin Lab,2016,62(10):1965-1972.
11 Chen P,Li J,Li J,et al.Dynamic effects of CYP3A5 polymorphism on dose requirement and trough concentration of tacrolimus in renal transplant recipients.J Clin Pharm Ther,2017,42(1):93-97.
12 Birdwell KA,Decker B,Barbarino JM,et al.Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing.Clin Pharmacol Ther,2015,98(1):19-24.
13 方洁,陈冰,张伟霞,等.肾移植中环孢素的血药浓度与多药耐药基因多态性的关系.中国临床药学杂志,2008,17(5):265-269.
14 Staatz CE,Goodman LK,Tett SE.Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the p￣h￣a￣r￣m￣a￣c￣o￣k￣i￣n￣e￣t￣i￣c￣s and p￣h￣a￣r￣m￣a￣c￣o￣d￣y￣n￣a￣m￣i￣c￣s of calcineurin inhibitors:Part I.Clin Pharmacokinet,2010,49(3):141-175.
15 杜迪,李维亮,辛华雯.环孢素A的药物基因组学研究进展.中国药师,2018,21(04):695-700.
16 Tang HL,Ma LL,Xie HG,et al.Effects of the CYP3A5*3 variant on cyclosporine exposure and acute rejection rate in renal transplant patients:a meta-analysis.Pharmacogenet Genomics,2010,20(9):525-531.
17 Patterson TF,Thompson GR,Denning DW,et al.Practice Guidelines for the Diagnosis and Management of Aspergillosis:2016 Update by the Infectious Diseases Society of America.Clin Infect Dis,2016,63(4):e1-e60.
18 Pappas PG,Kauffman CA,Andes DR,et al.Clinical Practice Guideline for the Management of Candidiasis:2016 Update by the Infectious Diseases Society of America.Clin Infect Dis,2016,62(4):e1-50.
19 Hyland R,Jones BC,Smith DA.Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole.Drug Metab Dispos,2003,31(5):540-547.
20 Moriyama B,Obeng AO,Barbarino J,et al.Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy.Clin Pharmacol Ther,2017,102(1):45-51.
21 曲洪澜,郭丹丹,徐婷,等.CYP2C19基因多态性对血液病患者伏立康唑血药浓度的影响及血药浓度监测在侵袭性真菌病防治中的价值.中华血液学杂志,2018,39(3):202-206.
22 Ashbee HR,Barnes RA,Johnson EM,et al.Therapeutic drug monitoring (TDM) of antifungal agents:guidelines from the British Society for Medical Mycology.J Antimicrob Chemother,2014,69(5):1162-1176.
23 Lestner J,Hope WW.Itraconazole:an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections.Expert Opin Drug Metab Toxicol,2013,9(7):911-926.
24 Brammer KW,Farrow PR,Faulkner JK.Pharmacokinetics and tissue penetration of fluconazole in humans.Rev Infect Dis,1990,12 Suppl 3:S318-326.
25 Brüggemann RJ,Alffenaar JW,Blijlevens NM,et al.Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents.Clin Infect Dis,2009,48(10):1441-1458.
26 Vanhove T,Bouwsma H,Hilbrands L,et al.Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients.Am J Transplant,2017,17(9):2372-2380.
27 Groll AH,Townsend R,Desai A,et al.Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4.Transpl Infect Dis,2017,19(5).
28 Zhang S,Pillai VC,Mada SR,et al.Effect of voriconazole and other azole antifungal agents on CYP3A activity and metabolism of tacrolimus in human liver microsomes.Xenobiotica,2012,42(5):409-416.
29 Imamura CK,Furihata K,Okamoto S,et al.Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole.J Clin Pharmacol,2016,56(4):408-413.
30 Iwamoto T,Monma F,Fujieda A,et al.Effect of Genetic Polymorphism of CYP3A5 and CYP2C19 and Concomitant Use of Voriconazole on Blood Tacrolimus Concentration in Patients Receiving Hematopoietic Stem Cell Transplantation.Ther Drug Monit,2015,37(5):581-588.
31 Lempers VJ,Martial LC,Schreuder MF,et al.Drug-interactions of azole antifungals with selected immunosuppressants in transplant patients:strategies for optimal management in clinical practice.Curr Opin Pharmacol,2015,24:38-44.