title: Identification of factors affecting tacrolimus level and 5-year clinical outcome in kidney transplant patients.
abstract: The purpose of this study was to identify and characterize the association of various clinical variables and CYP3A5 genotypes with the pharmacokinetics of tacrolimus and outcome over 1-5 years in kidney transplantation patients in Korea. A total of 129 recipients (aged 18-65 years) administered tacrolimus were genotyped for CYP3A5 (6986A>G in intron 3; rs776746). Clinical covariates and trough levels, doses and dose-adjusted trough levels of tacrolimus, as well as complications during the 1-5 years after transplantation, were analysed. A linear mixed model was used to investigate potential factors affecting the trough levels, doses and dose-adjusted levels of tacrolimus. We identified factors affecting chronic allograft nephropathy (CAN) and tacrolimus-related complications. After adjusting for sex, body-weight and doses of corticosteroids and mycophenolate mofetil, we noted that CYP3A5 genotypes had the most profound effect on the dose and dose-adjusted trough levels of tacrolimus 1-5 years after transplantation (p < 0.001). Trough levels of tacrolimus were associated with post-transplantation hyperlipidaemia (p < 0.05), and estimated glomerular filtration rate was associated with CAN (p < 0.05). Therefore, the CYP3A5 genotype is a variable marker for tacrolimus dose requirement, and the trough level of tacrolimus should be controlled to minimize post-transplant hyperlipidaemia to achieve optimum outcome.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: In-Wha
authors.initials: IW
authors.lastname: Kim
authors.forename: Hyejin
authors.initials: H
authors.lastname: Noh
authors.forename: Eunhee
authors.initials: E
authors.lastname: Ji
authors.forename: Nayoung
authors.initials: N
authors.lastname: Han
authors.forename: Su Hyun
authors.initials: SH
authors.lastname: Hong
authors.forename: Jongwon
authors.initials: J
authors.lastname: Ha
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Burckart
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Oh
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D016030:Kidney Transplantation / Q000379:methods*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D056910:Republic of Korea; D012189:Retrospective Studies; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D009173:Mycophenolic Acid; D016559:Tacrolimus