title: Associations of HSD11B1 polymorphisms with tacrolimus concentrations in Chinese renal transplant recipients with prednisone combined therapy.
abstract: Tacrolimus requires close therapeutic drug monitoring because of its narrow therapeutic index and marked interindividual pharmacokinetic variation. In this study, we investigated the associations of polymorphisms in the gene encoding 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) with tacrolimus concentrations in Chinese renal transplant recipients during the early posttransplantation stage. A total of 258 renal transplant recipients receiving tacrolimus with prednisone (30 mg) combined therapy were genotyped for HSD11B1 rs846908, rs846910, rs4844880, and CYP3A5*3 polymorphisms. Tacrolimus trough concentrations were determined on days 6-9 after transplantation, measured by a chemiluminescent microparticle immunoassay. Among the CYP3A5 expressers, the dose-adjusted trough concentration (C0/D) of tacrolimus in HSD11B1 rs846908 AA homozygous individuals was considerably lower than found in GG+GA carriers [56.2 (23.9-86.6) versus 76.7 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0204]; HSD11B1 rs846910 AA homozygotes had a lower tacrolimus C0/D compared with GG+GA carriers [51.2 (23.9-86.6) versus 76.3 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0367]; carriers with the HSD11B1 rs4844880 AA genotype had a significantly lower tacrolimus C0/D with respect to carriers of TT+TA genotypes [61.3 (23.9-97.5) versus 77.2 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0002]; the HSD11B1 AA-AA-AA haplotype carriers had a lower tacrolimus C0/D than noncarriers [51.2 (23.9-86.6) versus 76.3 (12.6-220.0) (ng/ml)/(mg/kg), P = 0.0367]. These findings illustrate that the HSD11B1 genotypes are closely correlated with tacrolimus trough concentrations, suggesting that these polymorphisms may be useful for safer dosing of tacrolimus.
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China.
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China.
authors.forename: Xueding
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China huangmin@mail.sysu.edu.cn wcx6363@163.com.
authors.forename: Changxi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (X.L., J.L., S.L., Y.Z., X.W., C.Z., M.H.); Kidney Transplant Department, Transplant Center, First Affiliated Hospital, Sun Yat-sen University (Q.F., H.W., J.L., C.W.); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine (S.L.); School of Pharmaceutical Sciences, Guangzhou Medical University (Y.Z.), Guangzhou, People's Republic of China huangmin@mail.sysu.edu.cn wcx6363@163.com.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics*; D000328:Adult; D002681:China; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011241:Prednisone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D011241:Prednisone; D016559:Tacrolimus