The recovery time-course of CYP3A after induction by St John's wort administration

Abstract

What is already known about this subject: St John's wort causes the induction of CYP3A. Little is known about how long the effect remains after cessation of St John's wort.

What this study adds: The in vivo CYP3A activity returns progressively to the basal level approximately 1 week after cessation of St John's wort administration

Aims: To examine the recovery time course of CYP3A after enzyme induction by St John's wort administration.

Methods: The subjects were 12 healthy men, aged 20-33 years. On the first day, they received an oral dose of midazolam 5 mg without St John's wort (day -14). From the next day, they took St John's wort for 14 days. On the last day of St John's wort treatment (day 0) and 3 and 7 days after completion of St John's wort treatment (days 3 and 7), they received the same dose of midazolam. On each day, blood samples were obtained until 8 h after midazolam administration. Plasma concentrations of midazolam were measured by HPLC. Pharmacokinetic parameters of midazolam were determined using noncompartmental analysis.

Results: Apparent oral clearance of midazolam was significantly increased after St John's wort administration from 65.3 +/- 8.4 l h(-1) (day -14) to 86.8 +/- 17.3 l h(-1) (day 0). It returned to the control level 7 days after the completion of St John's wort (day 7, 59.7 +/- 3.8 l h(-1)). No significant difference in the elimination half-life between the four periods of the study was observed. The changes in apparent oral clearance after St John's wort discontinuation indicated that CYP3A activity recovers from enzyme induction with an estimated half-life of 46.2 h.

Conclusions: CYP3A activity induced by St John's wort administration progressively returns to the basal level after approximately 1 week. This finding may provide useful information to avoid clinically significant interactions of St John's wort with CYP3A substrates.

Figure 1

A scheme of the study design. Arrows represent midazolam (MDZ) dosing. SJW: St John's wort

Figure 2

Mean (±SEM) plasma concentrations of midazolam on day 0 (□) (A), day 3 (▵) (B), and day 7 (×) (C) compared with day −14 (•) (control) in 12 subjects

Figure 3

Individual changes of apparent oral clearance ratio (vs. day −14 as control) after completion of St John's wort (SJW) administration. Bold line represents a recovery process curve of apparent oral clearance ratio calculated from point estimates by nonlinear regression analysis