The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol.
OBJECTIVE
A single-nucleotide polymorphism (SNP) of the human multidrug-resistance gene in wobble position of exon 26 reportedly predicts expression and function of P-glycoprotein in human enterocytes and lymphocytes. Several other allelic variants of MDR1 have been identified, some of which lead to amino acid exchange with as yet unknown functional relevance.


METHODS
In healthy white volunteers, we investigated the influence of the hereditary variants C3435T in exon 26 and G2677T/A (Ala893Ser/Thr) in exon 21 and the influence of 7 frequent or putative functional SNPs on duodenal MDR1 messenger ribonucleic acid (n = 32) and immunoreactive P-glycoprotein (n = 37) expression. Moreover, the disposition of the probe drug talinolol was evaluated in 55 subjects after oral administration (100 mg) and in 23 subjects after intravenous administration(30 mg).


RESULTS
Duodenal MDR1 messenger ribonucleic acid and P-glycoprotein, as assessed by real-time polymerase chain reaction (TaqMan) and immunostaining, were not influenced by any MDR1 polymorphism studied. Talinolol disposition was not affected by the exon 26 mutation C3435T. In carriers of the TT/TA variants of G2677T/A, the area under the serum concentration-time curve values of oral talinolol were slightly but significantly elevated compared with those in carriers of at least 1 wild-type allele (P <.05, Kruskal-Wallis test; P =.014, Mann-Whitney U test). However, multiple comparisons with combinations of putative functional SNPs did not confirm a significant influence of the MDR1 genotype on talinolol disposition.


CONCLUSIONS
We did not identify any influence of MDR1 genotypes on duodenal expression of P-glycoprotein and disposition of talinolol in humans.
Siegmund
Werner
W
Department of Clinical Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Greifswald, Germany. siegmuw@uni-greifswald.de
Ludwig
Karen
K
Giessmann
Thomas
T
Dazert
Peter
P
Schroeder
Eike
E
Sperker
Bernhard
B
Warzok
Rolf
R
Kroemer
Heyo K
HK
Cascorbi
Ingolf
I
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis* / Q000235:genetics; D000328:Adult; D019540:Area Under Curve; D004386:Duodenum / Q000737:chemistry*; D005260:Female; D019450:Genes, MDR; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000032:analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011412:Propanolamines; D012333:RNA, Messenger; C011550:talinolol