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

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 (R)). 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 ( C-max), and time to reach C-max were not significantly altered. After intravenous talinolol, SJW affected only CLNR ( 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.