Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors' dose requirements and trough blood levels in stable renal transplant patients.

AIMS CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the immunosuppressants tacrolimus (Tac) and cyclosporine (CsA). The objective of the study was to assess the potential influence of a new functional SNP in CYP3A4 on the pharmacokinetic parameters assessed by dose requirements and trough blood levels of both calcineurin inhibitors (CNI) in stable renal transplant patients. PATIENTS & METHODS A total of 99 stable renal transplant patients receiving either Tac (n = 49) or CsA (n = 50) were genotyped for the CYP3A4 intron 6 C>T (rs35599367) and CYP3A5*3 SNPs. Trough blood levels ([Tac](0) or [CsA](0) in ng/ml), dose-adjusted [Tac](0) or [CsA](0) (ng/ml per mg/kg bodyweight) as well as doses (mg/kg bodyweight) required to achieve target concentrations were compared among patients according to allelic status for CYP3A4 and CYP3A5. RESULTS Dose-adjusted concentrations were 2.0- and 1.6-fold higher in T-variant allele carriers for the CYP3A4 intron 6 C>T SNP compared with homozygous CC for Tac and CsA, respectively. When CYP3A4/CYP3A5 genotypes were combined, the difference was even more striking as the so-defined CYP3A poor metabolizer group presented dose-adjusted concentration 1.6- and 4.1-fold higher for Tac, and 1.5- and 2.2-fold higher for CsA than the intermediate metabolizer and extensive metabolizer groups, respectively. Multiple linear regression analysis revealed that, taken together, both CYP3A4 intron 6 and CYP3A5*3 SNPs explained more than 60 and 20% of the variability observed in dose-adjusted [Tac](0) and [CsA](0), respectively. CONCLUSION The CYP3A4 intron 6 C>T polymorphism is associated with altered Tac and CsA metabolism. CYP3A4 intron 6 C>T along with CYP3A5*3 (especially for Tac) pharmacogenetic testing performed just before transplantation may help identifying patients at risk of CNI overexposure and contribute to limit CNI-related nephrotoxicity by refining the starting dose according to their genotype. Original submitted 5 May 2011; Revision submitted 29 June 2011.

[1]  V. Haufroid,et al.  A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients. , 2011, Clinical chemistry.

[2]  W. Sadee,et al.  Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs , 2011, The Pharmacogenomics Journal.

[3]  D. Kuypers.  Pharmacogenetic vs. Concentration‐Controlled Optimization of Tacrolimus Dosing in Renal Allograft Recipients , 2010, Clinical pharmacology and therapeutics.

[4]  M. Loriot,et al.  Optimization of Initial Tacrolimus Dose Using Pharmacogenetic Testing , 2010, Clinical pharmacology and therapeutics.

[5]  C. Eap,et al.  CYP3A7, CYP3A5, CYP3A4, and ABCB1 Genetic Polymorphisms, Cyclosporine Concentration, and Dose Requirement in Transplant Recipients , 2008, Therapeutic drug monitoring.

[6]  Zheng Jiao,et al.  Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients , 2008, European Journal of Clinical Pharmacology.

[7]  H. Lou,et al.  Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients. , 2008, Transplantation proceedings.

[8]  J. D. de Fijter,et al.  CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients , 2008, Pharmacogenetics and genomics.

[9]  V. Haufroid,et al.  1199G>A and 2677G>T/A polymorphisms of ABCB1 independently affect tacrolimus concentration in hepatic tissue after liver transplantation , 2007, Pharmacogenetics and genomics.

[10]  P. Nürnberg,et al.  Sex-dependent genetic markers of CYP3A4 expression and activity in human liver microsomes. , 2007, Pharmacogenomics.

[11]  Guang-Ji Wang,et al.  Influence of CYP3A5 genetic polymorphism on cyclosporine A metabolism and elimination in Chinese renal transplant recipients , 2006, Acta Pharmacologica Sinica.

[12]  Zhaoqian Liu,et al.  EFFECTS OF GENETIC POLYMORPHISMS OF CYP3A4, CYP3A5 AND MDR1 ON CYCLOSPORINE PHARMACOKINETICS AFTER RENAL TRANSPLANTATION , 2006, Clinical and experimental pharmacology & physiology.

[13]  V. Haufroid,et al.  CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines from an Experimental Study , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  M. Hebert,et al.  EFFECT OF CYP3A5 POLYMORPHISM ON TACROLIMUS METABOLIC CLEARANCE IN VITRO , 2006, Drug Metabolism and Disposition.

[15]  Michael Oellerich,et al.  Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. , 2005, Clinical chemistry.

[16]  D. Holt,et al.  Tacrolimus Pharmacogenetics: The CYP3A5*1 Allele Predicts Low Dose-Normalized Tacrolimus Blood Concentrations in Whites and South Asians , 2005, Transplantation.

[17]  W. Weimar,et al.  Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the MDR‐1, CYP3A4, and CYP3A5 genes , 2004, Clinical pharmacology and therapeutics.

[18]  Yang Dai,et al.  In vitro metabolism of cyclosporine A by human kidney CYP3A5. , 2004, Biochemical pharmacology.

[19]  T. Habuchi,et al.  Influence of CYP3A5 and MDR1 (ABCB1) Polymorphisms on the Pharmacokinetics of Tacrolimus in Renal Transplant Recipients , 2004, Transplantation.

[20]  H. McLeod,et al.  CYP3A5 Polymorphism and the Ethnic Differences in Cyclosporine Pharmacokinetics in Healthy Subjects 1 , 2004, Therapeutic drug monitoring.

[21]  S. Masuda,et al.  CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation. , 2004, Pharmacogenetics.

[22]  J. Squifflet,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. , 2004, Pharmacogenetics.

[23]  B. Griffith,et al.  Tacrolimus Dosing in Adult Lung Transplant Patients Is Related to Cytochrome P4503A5 Gene Polymorphism , 2004, Journal of clinical pharmacology.

[24]  P. Beaune,et al.  Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients12 , 2003, Transplantation.

[25]  Peter Neuhaus,et al.  Sex is a major determinant of CYP3A4 expression in human liver , 2003, Hepatology.

[26]  W. Weimar,et al.  Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR‐1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus , 2003, Clinical pharmacology and therapeutics.

[27]  P. Beaune,et al.  Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. , 2003, Journal of the American Society of Nephrology : JASN.

[28]  B. Meibohm,et al.  The Effect of CYP3A5 and MDR1 Polymorphic Expression on Cyclosporine Oral Disposition in Renal Transplant Patients , 2003, Journal of clinical pharmacology.

[29]  M. Ingelman-Sundberg,et al.  Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[30]  E. Schuetz,et al.  Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[31]  Danielson Pb,et al.  The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. , 2002 .

[32]  E. Schuetz,et al.  Genetic contribution to variable human CYP3A-mediated metabolism. , 2002, Advanced drug delivery reviews.

[33]  J. Brockmöller,et al.  Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[34]  Julie A. Johnson,et al.  THE EFFECT OF GUT METABOLISM ON TACROLIMUS BIOAVAILABILITY IN RENALTRANSPLANT RECIPIENTS1,2 , 2001, Transplantation.

[35]  Ann Daly,et al.  Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression , 2001, Nature Genetics.

[36]  M. Ingelman-Sundberg,et al.  Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5'-upstream regulatory region. , 1999, Biochemical and biophysical research communications.

[37]  P. Wallemacq,et al.  Evaluation of the new AxSYM cyclosporine assay: comparison with TDx monoclonal whole blood and Emit cyclosporine assays. , 1999, Clinical chemistry.

[38]  L. Shaw,et al.  THERAPEUTIC DRUG MONITORING OF CYCLOSPORINE AND TACROLIMUS , 1998 .

[39]  U. Christians,et al.  Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[40]  H. Yamazaki,et al.  Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. , 1994, The Journal of pharmacology and experimental therapeutics.

[41]  L. Bowers.  Therapeutic monitoring for cyclosporine: difficulties in establishing a therapeutic window. , 1991, Clinical biochemistry.

[42]  Qi Li,et al.  Genetic polymorphisms of CYP3A5 genes and concentration of the cyclosporine and tacrolimus. , 2005, Transplantation proceedings.

[43]  C. Staatz,et al.  Clinical Pharmacokinetics and Pharmacodynamics of Tacrolimus in Solid Organ Transplantation , 2004, Clinical pharmacokinetics.