title: Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene.
abstract: OBJECTIVE
  We investigated the effect of polymorphisms in the P-glycoprotein (P-gp) MDR1 gene on steady-state pharmacokinetics of digoxin in Caucasians. According to earlier data, homozygous TT of the exon 26 complementary deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P-gp expression in the human intestine.
  
  
  METHODS
  Eight healthy male homozygous carriers of the wild-type exon-26 3435C>T (CC), 8 heterozygous subjects (CT), and 8 homozygous mutant (TT) subjects were selected. Seven further MDR1 polymorphisms were determined. Digoxin was administered orally twice daily on the first two study days; on days 3 to 5, 0.25 mg was given in the morning. On day 5, kinetic parameters were analyzed for genotype-phenotype and haplotype-phenotype relationships.
  
  
  RESULTS
  The area under the plasma concentration-time curve from time zero to 4 hours [AUC(0-4)] (P =.042) and C(max) (P =.043) values of digoxin were higher in subjects with the 3435TT genotype than in those with the 3435CC. No influence of other single nucleotide polymorphisms (SNPs) on digoxin parameters was detected. Comparison of genotypes deduced from SNPs 2677G>T (exon 21) and 3435C>T revealed significant differences for AUC(0-4) (P =.034) and C(max) (P =.039), which were substantiated by haplotype analysis. Haplotype 12 (2677G/3435T), which had a frequency of 13.3% in a randomly drawn Caucasian sample (n = 687), was associated (Mann-Whitney test) with higher AUC(0-4) values (P =.009) than were found in noncarriers (mean +/- SD, 5.7 +/- 0.9 microg. h/L [n = 7] versus 4.8 +/- 0.9 microg. h/L [n = 17]). Haplotype 11 (2677G/3435C) had lower AUC(0-4) values (P =.013) compared with those of noncarriers (mean +/- SD, 4.7 +/- 0.9 microg. h/L [n = 16] versus 5.6 +/- 0.9 microg. h/L [n = 8]). Results of haplotype analysis match data of other MDR1 studies.
  
  
  CONCLUSIONS
  Haplotype 12 codes for high values of AUC(0-4) and C(max) of orally administered digoxin. Analysis of MDR1 haplotypes is superior to unphased SNP analysis to predict MDR1 phenotype.
authors.affiliation: Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University of Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Johne
authors.forename: Karla
authors.initials: K
authors.lastname: Köpke
authors.forename: Thomas
authors.initials: T
authors.lastname: Gerloff
authors.forename: Ingrid
authors.initials: I
authors.lastname: Mai
authors.forename: Stephan
authors.initials: S
authors.lastname: Rietbrock
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffmeyer
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kerb
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brinkmann
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
authors.forename: Ivar
authors.initials: I
authors.lastname: Roots
mesh_terms: D000818:Animals; D004077:Digoxin / Q000493:pharmacokinetics*; D005260:Female; D019450:Genes, MDR; D005838:Genotype; D006239:Haplotypes; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D004077:Digoxin