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Induction of Intestinal P‐glycoprotein by St John's Wort Reduces the Oral Bioavailability of Talinolol
Author(s) -
Schwarz U I,
Hanso H,
Oertel R,
Miehlke S,
Kuhlisch E,
Glaeser H,
Hitzl M,
Dresser G K,
Kim R B,
Kirch W
Publication year - 2007
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100191
Subject(s) - bioavailability , pharmacokinetics , cmax , pharmacology , p glycoprotein , cyp3a4 , oral administration , ex vivo , chemistry , medicine , cytochrome p450 , metabolism , in vitro , biochemistry , antibiotics , multiple drug resistance
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 (CL NR ), elimination half‐life, peak serum drug concentration ( C max ), and time to reach C max 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. Clinical Pharmacology & Therapeutics (2007) 81 , 669–678. doi: 10.1038/sj.clpt.6100191 ; published online 28 March 2007