肾移植术后糖皮质激素和他克莫司的药代动力学相互作用（英文）
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摘要
糖皮质激素由于是CYP3A4和P-gp的诱导剂与他克莫司(tacrolimus,TAC)存在相互作用。但是,目前研究中的糖皮质激素剂量均为低剂量而非冲击剂量。本研究回顾性的研究63名肾移植术后患者,根据患者服用的糖皮质激素剂量进行分组:500 mg (术后1–3天), 30 mg (术后4–10天), 25 mg (术后11–17天), 20 mg (术后18–24天), 15 mg (术后25–31天),10 mg (术后32–60天)和10 mg (术后61–90天)。我们每日详细记录患者从手术至术后90天的患者检验和用药信息。研究发现:术后3个月内,不同糖皮质激素剂量下TAC的血药浓度无显著性差异,但是随着糖皮质激素的剂量减低, TAC的平均每日剂量显著性降低。同时,术后1–4天内,TAC每日的剂量没有变化,但是当糖皮质激素的剂量由500mg减为30mg时,TAC的浓度显著降低。本研究验证了低剂量的糖皮质激素对TAC的诱导效应,同时发现高剂量糖皮质激素和他克莫司合用时,糖皮质激素可能起到相关作用,为竞争性底物效果。因此在肾移植术后受者的糖皮质激素剂量发生变化时,监测TAC的血药浓度是有必要的。
There is an interaction between tacrolimus(TAC) and glucocorticoids where glucocorticoids is a known CYP3A4 and P-gp inducer.However, the dose of glucocorticoids reported is low but not pulse therapy.We retrospectively studied 63 renal transplant recipients receiving TAC after transplantation.All the patients were classified as 500 mg(POD 1–3), 30 mg(POD 4–10), 25 mg(POD 11–17), 20 mg(POD 18–24), 15 mg(POD 25–31), 10 mg(POD 32–60) and 10 mg(POD 61–90).We recorded daily data for each patient from the day of transplantation until POD 90.There was no difference in TAC blood levels within the 3 months after transplantation in the glucocorticoids groups.However, the average daily dose of TAC was significantly lower by weekly reductions of 5 mg dose.The TAC daily dose was not changed from POD 1–4, but the blood concentrations of TAC were significantly lower after the glucocorticoid dose was changed from 500 mg to 30 mg.We demonstrated the induction effect of low-dose glucocorticoids on TAC in renal transplant recipients, and found that the high-dose of glucocorticoids might play a role in substrate competition.We proposed that monitoring of the blood concentrations of TAC was needed when the glucocorticoid dose was changed in the patient undergoing renal transplantation.
There is an interaction between tacrolimus(TAC) and glucocorticoids where glucocorticoids is a known CYP3A4 and P-gp inducer.However, the dose of glucocorticoids reported is low but not pulse therapy.We retrospectively studied 63 renal transplant recipients receiving TAC after transplantation.All the patients were classified as 500 mg(POD 1–3), 30 mg(POD 4–10), 25 mg(POD 11–17), 20 mg(POD 18–24), 15 mg(POD 25–31), 10 mg(POD 32–60) and 10 mg(POD 61–90).We recorded daily data for each patient from the day of transplantation until POD 90.There was no difference in TAC blood levels within the 3 months after transplantation in the glucocorticoids groups.However, the average daily dose of TAC was significantly lower by weekly reductions of 5 mg dose.The TAC daily dose was not changed from POD 1–4, but the blood concentrations of TAC were significantly lower after the glucocorticoid dose was changed from 500 mg to 30 mg.We demonstrated the induction effect of low-dose glucocorticoids on TAC in renal transplant recipients, and found that the high-dose of glucocorticoids might play a role in substrate competition.We proposed that monitoring of the blood concentrations of TAC was needed when the glucocorticoid dose was changed in the patient undergoing renal transplantation.
引文
[1]Anglicheau,D.;Flamant,M.;Schlageter,M.H.;Martinez,F.;Cassinat,B.;Beaune,P.;Legendre,C.;Thervet,E.Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation.Nephrol.Dial.Transplant.2003,18,2409-2414.
[2]Filler,G.;Grygas,R.;Mai,I.;Stolpe,H.J.;Greiner,C.;Bauer,S.;Ehrich,J.H.Pharmacokinetics of tacrolimus(FK 506)in children and adolescents with renal transplants.Nephrol.Dial.Transplant.1997,12,1668-1671.
[3]Lampen,A.;Christians,U.;Guengerich,F.P.;Watkins,P.B.;Kolars,J.C.;Bader,A.;Gonschior,A.K.;Dralle,H.;Hackbarth,I.;Sewing,K.F.Metabolism of the immunosuppressant tacrolimus in the small intestine:cytochrome P450,drug interactions,and interindividual variability.Drug Metab.Dispos.1995,23,1315-1324.
[4]Tanaka,K.;Hirai,M.;Tanigawara,Y.;Yasuhara,M.;Hori,R.;Ueda,K.;Inui,K.Effect of cyclosporin analogues and FK506 on transcellular transport of daunorubicin and vinblastine via P-glycoprotein.Pharm.Res.1996,13,1073-1077.
[5]Organ Procurement and Transplantation Network(OPTN)and Scientific Registry of Transplant Recipients(SRTR).OPTN/SRTR 2010 Annual Data Report.Rockville,MD:Department of Health and Human Services,Health Resources and Services Administration,Healthcare Systems Bureau,Division of Transplant,2011,24.
[6]Hesselink,D.A.;Ngyuen,H.;Wabbijn,M.;Gregoor,P.J.;Steyerberg,E.W.;van Riemsdijk,I.C.;Weimar,W.;van Gelder,T.Tacrolimus dose requirement in renal transplant recipients is significantly higher when used in combination with corticosteroids.Br.J.Clin.Pharmacol.2003,56,327-330.
[7]Shihab,F.S.;Lee,S.T.;Smith,L.D.;Woodle,E.S.;Pirsch,J.D.;Gaber,A.O.;Henning,A.K.;Reisfield,R.;Fitzsimmons,W.;Holman,J.First for the Astellas Corticosteroid Withdrawal Group.Effect of corticosteroid withdrawal on tacrolimus and mycophenolate mofetil exposure in a randomized multicenter study.Am.J.Transplant.2013,13,474-484.
[8]van Duijnhoven,E.M.;Boots,J.M.;Christiaans,M.H.;Stolk,L.M.;Undre,N.A.;van Hooff,J.P.Increase in tacrolimus trough levels after steroid withdrawal.Transpl.Int.2003,16,721-725.
[9]Smith,LD.;Allard,JA.;Corbett,J.;Nelson,E.;Shihab,F.Tacrolimus nephrotoxicity as a result of steroid withdrawal in renal transplant recipients.Am.J.Transplant.2005,5(Suppl 11),159.
[10]Christians,U.;Jacobsen,W.;Benet,L.Z.;Lampen,A.Mechanisms of clinically relevant drug interactions associated with tacrolimus.Clin.Pharmacokinet.2002,41,813-851.
[11]Gibson,G.G.;Plant,N.J.;Swales,K.E.;Ayrton,A.;El-Sankary,W.Receptor-dependent transcriptional activation of cytochrome P4503A genes:Induction mechanisms,species differences and interindividual variation in man.Xenobiotica.2002,32,165-206.
[12]Geick,A.;Eichelbaum,M.;Burk,O.Nuclear receptor response elements mediate induction of intestinal MDR1by rifampin.J.Biol.Chem.2001,276,14581-14587.
[13]Undre,N.A.;Sch?fer,A.Factors affecting the pharmacokinetics of tacrolimus in the first year after renal transplantation.European Tacrolimus Multicentre Renal Study Group.Transplant.Proc.1998,30,1261-1263.
[14]Sinclair,N.R.Low-dose steroid therapy in cyclosporinetreated renal transplant recipients with well-functioning grafts.The Canadian Multicentre Transplant Study Group.CMAJ.1992,147,645-657.
[15]Kasiske,B.L.;Chakkera,H.A.;Louis,T.A.;Ma,J.Z.A meta-analysis of immunosuppression withdrawal trials in renal transplantation.J.Am.Soc.Nephrol.2000,11,1910-1917.
[16]Rostaing,L.;Cantarovich,D.;Mourad,G.;Budde,K.;Rigotti,P.;Mariat,C.;Margreiter,R.;Capdevilla,L.;Lang,P.;Vialtel,P.;Ortu?o-Mirete,J.;Charpentier,B.;Legendre,C.;Sanchez-Plumed,J.;Oppenheimer,F.;Kessler,M.Corticosteroid-free immunosuppression with tacrolimus,mycophenolate mofetil,and daclizumab induction in renal transplantation.Transplantation.2005,79,807-814.
[17]Vítko,S.;Klinger,M.;Salmela,K.;Wlodarczyk,Z.;Tydèn,G.;Senatorski,G.;Ostrowski,M.;Fauchald,P.;Kokot,F.;Stefoni,S.;Perner,F.;Claesson,K.;Castagneto,M.;Heemann,U.;Carmellini,M.;Squifflet,J.P.;Weber,M.;Segoloni,G.;B?ckman,L.;Sperschneider,H.;Kr?mer,B.K.Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation:Results of the Atlas study.Transplantation.2005,80,1734-1741.
[18]Serrano,O.K.;Kandaswamy,R.;Gillingham,K.;Chinnakotla,S.;Dunn,T.B.;Finger,E.;Payne,W.;Ibrahim,H.;Kukla,A.;Spong,R.;Issa,N.;Pruett,T.L.;Matas,A.Rapid discontinuation of prednisone in kidney transplant recipients:15-year outcomes from the university of minnesota.Transplantation.2017,101,2590-2598.
[19]Khwaja,K.;Asolati,M.;Harmon,J.;Melancon,J.K.;Dunn,T.;Gillingham,K.;Kandaswamy,R.;Humar,A.;Gruessner,R.;Payne,W.;Najarian,J.;Dunn,D.;Sutherland,D.;Matas,A.J.Outcome at 3 years with a prednisone-free maintenance regimen:a single-center experience with 349 kidney transplant recipients.Am.J.Transplant.2004,4,980-987.
[20]Matas,A.J.;Kandaswamy,R.;Gillingham,K.J.;McHugh,L.;Ibrahim,H.;Kasiske,B.;Humar,A.Prednisone-free maintenance immunosuppression-a 5-year experience.Am.J.Transplant.2005,5,2473-2478.
[21]Rizzari,M.D.;Suszynski,T.M.;Gillingham,K.J.;Dunn,T.B.;Ibrahim,H.N.;Payne,W.D.;Chinnakotla,S.;Finger,E.B.;Sutherland,D.E.;Kandaswamy,R.;Najarian,J.S.;Pruett,T.L.;Kukla,A.;Spong,R.;Matas,A.J.Ten-year outcome after rapid discontinuation of prednisone in adult primary kidney transplantation.Clin.J.Am.Soc.Nephrol.2012,7,494-503.
[2]Filler,G.;Grygas,R.;Mai,I.;Stolpe,H.J.;Greiner,C.;Bauer,S.;Ehrich,J.H.Pharmacokinetics of tacrolimus(FK 506)in children and adolescents with renal transplants.Nephrol.Dial.Transplant.1997,12,1668-1671.
[3]Lampen,A.;Christians,U.;Guengerich,F.P.;Watkins,P.B.;Kolars,J.C.;Bader,A.;Gonschior,A.K.;Dralle,H.;Hackbarth,I.;Sewing,K.F.Metabolism of the immunosuppressant tacrolimus in the small intestine:cytochrome P450,drug interactions,and interindividual variability.Drug Metab.Dispos.1995,23,1315-1324.
[4]Tanaka,K.;Hirai,M.;Tanigawara,Y.;Yasuhara,M.;Hori,R.;Ueda,K.;Inui,K.Effect of cyclosporin analogues and FK506 on transcellular transport of daunorubicin and vinblastine via P-glycoprotein.Pharm.Res.1996,13,1073-1077.
[5]Organ Procurement and Transplantation Network(OPTN)and Scientific Registry of Transplant Recipients(SRTR).OPTN/SRTR 2010 Annual Data Report.Rockville,MD:Department of Health and Human Services,Health Resources and Services Administration,Healthcare Systems Bureau,Division of Transplant,2011,24.
[6]Hesselink,D.A.;Ngyuen,H.;Wabbijn,M.;Gregoor,P.J.;Steyerberg,E.W.;van Riemsdijk,I.C.;Weimar,W.;van Gelder,T.Tacrolimus dose requirement in renal transplant recipients is significantly higher when used in combination with corticosteroids.Br.J.Clin.Pharmacol.2003,56,327-330.
[7]Shihab,F.S.;Lee,S.T.;Smith,L.D.;Woodle,E.S.;Pirsch,J.D.;Gaber,A.O.;Henning,A.K.;Reisfield,R.;Fitzsimmons,W.;Holman,J.First for the Astellas Corticosteroid Withdrawal Group.Effect of corticosteroid withdrawal on tacrolimus and mycophenolate mofetil exposure in a randomized multicenter study.Am.J.Transplant.2013,13,474-484.
[8]van Duijnhoven,E.M.;Boots,J.M.;Christiaans,M.H.;Stolk,L.M.;Undre,N.A.;van Hooff,J.P.Increase in tacrolimus trough levels after steroid withdrawal.Transpl.Int.2003,16,721-725.
[9]Smith,LD.;Allard,JA.;Corbett,J.;Nelson,E.;Shihab,F.Tacrolimus nephrotoxicity as a result of steroid withdrawal in renal transplant recipients.Am.J.Transplant.2005,5(Suppl 11),159.
[10]Christians,U.;Jacobsen,W.;Benet,L.Z.;Lampen,A.Mechanisms of clinically relevant drug interactions associated with tacrolimus.Clin.Pharmacokinet.2002,41,813-851.
[11]Gibson,G.G.;Plant,N.J.;Swales,K.E.;Ayrton,A.;El-Sankary,W.Receptor-dependent transcriptional activation of cytochrome P4503A genes:Induction mechanisms,species differences and interindividual variation in man.Xenobiotica.2002,32,165-206.
[12]Geick,A.;Eichelbaum,M.;Burk,O.Nuclear receptor response elements mediate induction of intestinal MDR1by rifampin.J.Biol.Chem.2001,276,14581-14587.
[13]Undre,N.A.;Sch?fer,A.Factors affecting the pharmacokinetics of tacrolimus in the first year after renal transplantation.European Tacrolimus Multicentre Renal Study Group.Transplant.Proc.1998,30,1261-1263.
[14]Sinclair,N.R.Low-dose steroid therapy in cyclosporinetreated renal transplant recipients with well-functioning grafts.The Canadian Multicentre Transplant Study Group.CMAJ.1992,147,645-657.
[15]Kasiske,B.L.;Chakkera,H.A.;Louis,T.A.;Ma,J.Z.A meta-analysis of immunosuppression withdrawal trials in renal transplantation.J.Am.Soc.Nephrol.2000,11,1910-1917.
[16]Rostaing,L.;Cantarovich,D.;Mourad,G.;Budde,K.;Rigotti,P.;Mariat,C.;Margreiter,R.;Capdevilla,L.;Lang,P.;Vialtel,P.;Ortu?o-Mirete,J.;Charpentier,B.;Legendre,C.;Sanchez-Plumed,J.;Oppenheimer,F.;Kessler,M.Corticosteroid-free immunosuppression with tacrolimus,mycophenolate mofetil,and daclizumab induction in renal transplantation.Transplantation.2005,79,807-814.
[17]Vítko,S.;Klinger,M.;Salmela,K.;Wlodarczyk,Z.;Tydèn,G.;Senatorski,G.;Ostrowski,M.;Fauchald,P.;Kokot,F.;Stefoni,S.;Perner,F.;Claesson,K.;Castagneto,M.;Heemann,U.;Carmellini,M.;Squifflet,J.P.;Weber,M.;Segoloni,G.;B?ckman,L.;Sperschneider,H.;Kr?mer,B.K.Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation:Results of the Atlas study.Transplantation.2005,80,1734-1741.
[18]Serrano,O.K.;Kandaswamy,R.;Gillingham,K.;Chinnakotla,S.;Dunn,T.B.;Finger,E.;Payne,W.;Ibrahim,H.;Kukla,A.;Spong,R.;Issa,N.;Pruett,T.L.;Matas,A.Rapid discontinuation of prednisone in kidney transplant recipients:15-year outcomes from the university of minnesota.Transplantation.2017,101,2590-2598.
[19]Khwaja,K.;Asolati,M.;Harmon,J.;Melancon,J.K.;Dunn,T.;Gillingham,K.;Kandaswamy,R.;Humar,A.;Gruessner,R.;Payne,W.;Najarian,J.;Dunn,D.;Sutherland,D.;Matas,A.J.Outcome at 3 years with a prednisone-free maintenance regimen:a single-center experience with 349 kidney transplant recipients.Am.J.Transplant.2004,4,980-987.
[20]Matas,A.J.;Kandaswamy,R.;Gillingham,K.J.;McHugh,L.;Ibrahim,H.;Kasiske,B.;Humar,A.Prednisone-free maintenance immunosuppression-a 5-year experience.Am.J.Transplant.2005,5,2473-2478.
[21]Rizzari,M.D.;Suszynski,T.M.;Gillingham,K.J.;Dunn,T.B.;Ibrahim,H.N.;Payne,W.D.;Chinnakotla,S.;Finger,E.B.;Sutherland,D.E.;Kandaswamy,R.;Najarian,J.S.;Pruett,T.L.;Kukla,A.;Spong,R.;Matas,A.J.Ten-year outcome after rapid discontinuation of prednisone in adult primary kidney transplantation.Clin.J.Am.Soc.Nephrol.2012,7,494-503.
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