Induction of intestinal P-glycoprotein by St John's wort reduces the oral bioavailability of talinolol

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • U. I. Schwarz - , TUD Dresden University of Technology, Western University, Vanderbilt University (Author)
  • H. Hanso - , TUD Dresden University of Technology (Author)
  • R. Oertel - , Institute of Clinical Pharmacology (Author)
  • S. Miehlke - , TUD Dresden University of Technology (Author)
  • E. Kuhlisch - , TUD Dresden University of Technology (Author)
  • H. Glaeser - , Robert Bosch Krankenhaus Stuttgart (Author)
  • M. Hitzl - , Robert Bosch Krankenhaus Stuttgart (Author)
  • G. K. Dresser - , Western University (Author)
  • R. B. Kim - , Western University, Vanderbilt University (Author)
  • W. Kirch - , TUD Dresden University of Technology (Author)

Abstract

St John's wort (SJW) is known to induce cytochrome P450 (CYP) 3A4 and P-glycoprotein through pregnane X-receptor activation. Our study evaluated the effects of long-term SJW administration on oral and intravenous pharmacokinetics of the nonmetabolized in vivo probe of P-glycoprotein, talinolol, in relation to intestinal P-glycoprotein expression. In a controlled, randomized study (N=9), the pharmacokinetics of oral (50 mg) and intravenous talinolol (30 mg) was determined before and after 12 days SJW (900 mg daily, Jarsin 300®). Duodenal biopsies were taken and MDR1 genotypes assessed. SJW reduced the oral talinolol bioavailability by 25% (P=0.049) compared with water control. A 93% increase in oral clearance (P=0.177) and a 31% reduction in area under the serum concentration time curve (AUC; P=0.030) were observed. Renal and nonrenal clearance (CLNR), elimination half-life, peak serum drug concentration (Cmax), and time to reach Cmax were not significantly altered. After intravenous talinolol, SJW affected only CL NR (35% increase compared with water, P=0.006). SJW increased MDR1 messenger ribonucleic acid (mRNA) as well as P-glycoprotein levels in the duodenal mucosa. Subjects with the combined MDR1 genotype comprising 1236C>T, 2677G>T/A, and 3435C>T polymorphisms had lower intestinal MDR1 mRNA levels and displayed an attenuated inductive response to SJW as assessed by talinolol disposition. Long-term SJW decreased talinolol AUC with a corresponding increase in intestinal MDR1 expression, suggesting that SJW has a major inductive effect on intestinal P-glycoprotein. Interestingly, the magnitude of induction appeared to be affected by MDR1 genotype.

Details

Original languageEnglish
Pages (from-to)669-678
Number of pages10
JournalClinical Pharmacology and Therapeutics
Volume81
Issue number5
Publication statusPublished - May 2007
Peer-reviewedYes

External IDs

researchoutputwizard legacy.publication#18607
researchoutputwizard legacy.publication#19609
Scopus 34247244726
PubMed 17392718
ORCID /0000-0003-1526-997X/work/142247322

Keywords