title: Human intestinal P-glycoprotein activity estimated by the model substrate digoxin.
abstract: OBJECTIVE
  P-glycoprotein (Pgp) plays a part in the intestinal uptake of xenobiotics and has been associated with susceptibility to ulcerative colitis. The aim of this study was to examine Pgp activity in relation to age, gender, medical treatment (rifampicin or ketoconazole) and the multidrug resistance (MDR1) gene single nucleotide polymorphisms (SNPs) G2677T and C3435T using the model drug digoxin.
  
  
  METHODS
  Pgp activity was estimated from the pharmacokinetics of orally administered digoxin in blood samples from 32 healthy subjects. MDR1 gene expression in duodenal biopsies was monitored by real-time quantitative RT-PCR (RQ-PCR) and Western blot analyses. MDR1 SNPs were determined by PCR-restriction fragment length polymorphism (PCR-RFLP). The effect of medical treatment was tested by open, randomized, cross-over treatment with rifampicin and ketoconazole.
  
  
  RESULTS
  Rifampicin treatment resulted in increased Pgp activity, duodenal MDR1 mRNA expression and Pgp detection compared with that in the control group (p<0.05 for all), Pgp activity being associated with duodenal MDR1 mRNA level (p<0.05). Individuals homozygous for the 3435 wild-type allele (CC) showed higher Pgp activity (p<0.05), whereas SNP 2677 apparently did not affect Pgp activity. No variation in Pgp in relation to age or gender was found.
  
  
  CONCLUSIONS
  Our data confirm that rifampicin increases Pgp activity, by increasing MDR1 mRNA and Pgp levels. Moreover, we found that the wild-type allele of the synonymous polymorphism of MDR1 position 3435 confers a higher Pgp activity. These data support other findings suggesting an effect of Pgp on treatment response and disease susceptibility.
authors: Department of Internal Medicine, Viborg County Hospital, Viborg, Denmark.
authors: U L
authors: UL
authors: Larsen
authors: L
authors: L
authors: Hyldahl  Olesen
authors: C
authors: C
authors: Guldborg Nyvold
authors: J
authors: J
authors: Eriksen
authors: P
authors: P
authors: Jakobsen
authors: M
authors: M
authors: Østergaard
authors: H
authors: H
authors: Autrup
authors: V
authors: V
authors: Andersen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D004077:Digoxin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012293:Rifampin / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D012333:RNA, Messenger; D004077:Digoxin; D007654:Ketoconazole; D012293:Rifampin