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. CONCLUSION: 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. Copyright 2008 S. Karger AG, Basel.
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. CONCLUSION: 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. Copyright 2008 S. Karger AG, Basel.
Authors: Abdullah M Al-Mohizea; Khalid M Alkharfy; Khawla M Bagulb; Amal M Alghamdi; Fahad I Al-Jenoobi; Saleh Al-Muhsen; Rabih Halwani; Mohammad Khalid Parvez; M Khalid Parvez; Mohammed S Al-Dosari Journal: Mol Biol Rep Date: 2012-10-07 Impact factor: 2.316
Authors: Laura M Hodges; Svetlana M Markova; Leslie W Chinn; Jason M Gow; Deanna L Kroetz; Teri E Klein; Russ B Altman Journal: Pharmacogenet Genomics Date: 2011-03 Impact factor: 2.089
Authors: Joseph D Ma; Shirley M Tsunoda; Joseph S Bertino; Meghana Trivedi; Keola K Beale; Anne N Nafziger Journal: Clin Pharmacokinet Date: 2010-04 Impact factor: 6.447