title: Genetic differences in Native Americans and tacrolimus dosing after kidney transplantation.
abstract: Tacrolimus pharmacokinetics vary due to single nucleotide polymorphisms (SNPs) in metabolizing enzymes and membrane transporters that alter drug elimination. Clinically we observed that Native Americans require lower dosages of tacrolimus to attain trough levels similar to Caucasians. We previously demonstrated that Native Americans have decreased oral clearance of tacrolimus, suggesting that Native Americans may have more variant SNPs and, therefore, altered tacrolimus pharmacokinetic parameters. We conducted 12-hour pharmacokinetic studies on 24 adult Native American kidney transplant recipients on stable doses of tacrolimus for at least 1 month posttransplantation. Twenty-four Caucasian kidney transplant recipients were compared as controls. SNPs encoding the genes for the enzymes (CYP3A4, CYP3A5) and transporters (ABCB1, BCRP, and MRP1) were typed using TaqMan. The mean daily tacrolimus dose in the Native Americans was 0.03 ± 0.02 compared with the Caucasians 0.5 ± 0.3 (mg/kg/d; P = .002), with no significant differences in trough levels, (6.7 ± 3.1 vs 7.4 ± 2.1 ng/dL; P = .4). Many Native Americans, but not Caucasians, demonstrated the 3/*3 - C3435T CC and the *3/*3 -G2677T GG genotype combination previously associated with low tacrolimus dosing. Native Americans required significantly lower tacrolimus doses than Caucasians to achieve similar tacrolimus trough levels, in part due to lower tacrolimus clearance from decreased drug metabolism and excretion.
authors: Division of Nephrology, Mayo Clinic, Phoenix, Arizona 85054, USA. chakkera.harini@mavo.edu
authors: H A
authors: HA
authors: Chakkera
authors: Y-H
authors: YH
authors: Chang
authors: J K
authors: JK
authors: Bodner
authors: S
authors: S
authors: Behmen
authors: R L
authors: RL
authors: Heilman
authors: K S
authors: KS
authors: Reddy
authors: D C
authors: DC
authors: Mulligan
authors: A A
authors: AA
authors: Moss
authors: H
authors: H
authors: Khamash
authors: N
authors: N
authors: Katariya
authors: W R
authors: WR
authors: Hewitt
authors: T L
authors: TL
authors: Pitta
authors: L A
authors: LA
authors: Frassetto
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007198:Indians, North American; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000208:ethnology* / Q000235:genetics / Q000601:surgery*; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time 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; D016559:Tacrolimus