title: ABCB1 polymorphisms are associated with cyclosporine-induced nephrotoxicity and gingival hyperplasia in renal transplant recipients.
abstract: OBJECTIVE
  There is a great deal of controversy regarding the clinical impact of genetic variants in patients receiving cyclosporine (CsA) as immunosuppressant therapy. We have investigated the effect of polymorphisms in the CYP3A and ABCB1 genes on CsA pharmacokinetics, acute rejection incidence and drug-related side effects in renal transplant recipients
  
  
  METHODS
  The presence of CYP3A5*3, CYP3A4*1B and ABCB1 C1236T, G2677T/A and C3435T polymorphisms was assessed in 68 patients and retrospectively associated with pharmacokinetic and clinical parameters at 1 week and 1, 5 and 12 months after transplantation.
  
  
  RESULTS
  Only minor associations were found between the tested polymorphisms and CsA pharmacokinetics. Most notably, CYP3A5 expressers showed lower blood trough levels than non-expressers in the first week after grafting (32.5 ± 14.7 vs. 55.1 ± 3.8 ng/ml per mg/day per kilogram). In terms of CsA-induced adverse effects, the incidence of nephrotoxicity was higher in carriers of the ABCB1 3435TT genotype and in those patients carrying four to six variants in the three ABCB1 loci [odds ratio (OR) 4.2, 95 % confidence interval (CI) 1.3-13.9, p = 0.02 and OR 3.6, 95 % CI 1.1-11.8, p = 0.05, respectively]. These subjects with four to six ABCB1 variants were also at higher risk for gingival hyperplasia (OR 3.29, 95 % CI 1.1-10.3, p = 0.04). Renal function and the incidence of neurotoxicity and of acute rejection did not vary across the different genotypes.
  
  
  CONCLUSIONS
  ABCB1 polymorphisms may be helpful in predicting certain CsA-related side effects in renal transplant recipients. Our results also suggest that the mechanisms underlying these genetic associations are most likely independent of the drug's trough blood concentrations.
authors.affiliation: Department of Surgical and Medical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Av. Elvas s/n 06071, Badajoz, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: García
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Macías
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Cubero
authors.forename: Julio
authors.initials: J
authors.lastname: Benítez
authors.forename: Francisco
authors.initials: F
authors.lastname: Caravaca
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gervasini
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000704:Analysis of Variance; D016009:Chi-Square Distribution; D016572:Cyclosporine / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D016903:Drug Monitoring; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005885:Gingival Hyperplasia / Q000097:blood / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology*; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human