title: Impact of MDR1 haplotypes derived from C1236T, G2677T/A and C3435T on the pharmacokinetics of single-dose oral digoxin in healthy Chinese volunteers.
abstract: OBJECTIVE
  To investigate the effect of single-nucleotide polymorphisms (SNPs) and the haplotypes of MDR1 on the pharmacokinetics of single-dose digoxin in healthy Chinese volunteers.
  
  
  METHODS
  After the genotypes of the MDR1 alleles of interest (G1199A, C1236T, G2677T/A and C3435T) had been determined, 20 subjects with the predominant haplotypes (TTT, CGC, TGC and CAC, in the order of position 1236-2677-3435) were selected and administered with 0.25 mg of digoxin. Venous blood samples were taken from 0 to 4 h after dosing, and the pharmacokinetic parameters were calculated using the Drug and Statistics software.
  
  
  RESULTS
  No mutation allele of G1199A was found in this study, the frequencies of the C1236T, G2677T/A and C3435T genetic variants were 65.2, 41.2, 17.3 and 39.7%, respectively. The 4 haplotypes TTT, TGC, CGC and CAC were present in more than 90% of Chinese Han subjects, and an incomplete linkage between C3435T in exon 26, G2677T in exon 21 and C1236T in exon 12 was found. The peak concentration in plasma, the time to reach the peak concentration and the area under the plasma concentration/time curve between 0 and 4 h were used as indices of digoxin absorption. They were significantly different between subjects with the haplotypes TGC-CGC and those with TTT-TTT (p < 0.05). No significant difference was found when volunteers were grouped according to the haplotypes derived from G2677T and C3435T or disparate SNPs.
  
  
  CONCLUSIONS
  Our findings indicated that the MDR1 haplotype derived from C1236T, G2677T/A and C3435T is superior to predict the pharmacokinetics of digoxin. Digoxin pharmacokinetics are significantly different between individuals with the TTT-TTT haplotype and those with TGC-CGC.
authors.affiliation: Clinical Pharmacy and Pharmacology Research Institute, Second Xiangya Hospital of Central South University, Changsha, Hunan, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Jiang
authors.forename: Bi-Kui
authors.initials: BK
authors.lastname: Zhang
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Tu
authors.forename: Huan-De
authors.initials: HD
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics*; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D002681:China; D004077:Digoxin / Q000493:pharmacokinetics*; D005091:Exons; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D004077:Digoxin