期刊
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
卷 69, 期 6, 页码 656-662出版社
WILEY
DOI: 10.1111/j.1365-2125.2010.03624.x
关键词
CYP3A4; danshen extract; drug interaction; midazolam
资金
- Health Bureau of Shanghai Municipality [2008049]
- Shanghai Municipality, China [J50303]
- developing platform of clinical research technology of innovative drugs [2008ZX09312]
center dot Many cytochrome P450 mediated interactions have been reported between drug and herbal medicines. In particular, CYP3A4 is known to play a critical role in several clinically relevant herb-drug interactions. Midazolam has been reported to be one of the preferred in vivo CYP3A probes. center dot It has been reported that the lipophilic components of danshen could induce CYP3A in C57BL/6J mice, that cryptotanshinone and tanshinone IIA of danshen extract could activate human PXR and consequently induce the expression of the CYP3A4 gene. WHAT THIS STUDY ADDS center dot Co-administration of multiple doses of danshen tablets caused an increase in apparent oral clearance of midazolam by 35.4%, a corresponding decline in C-max by 31.1% and a decline in AUC(0,infinity) by 27.0% in human volunteers. The t(1/2) of midazolam and 1-hydroxymidazolam were not changed, and the C-max and AUC(0,infinity) ratio of midazolam to 1-hydroxymidazolam were not affected. The results suggested that multiple dose administration of danshen tablets could induce CYP3A4 in the gut, thereby increasing the clearance of midazolam. Therefore, caution should be taken when danshen products containing lipophilic components are used in combination with therapeutic drugs metabolized by CYP3A. AIMS To assess the effect of danshen extract on CYP3A4 activity using midazolam as an in vivo probe. METHODS A sequential, open-label, two-period pharmacokinetic interaction study design was used to compare midazolam pharmacokinetic parameters before and after 14 days of administration of danshen tablets. Twelve healthy volunteers received a single oral dose (15 mg) of midazolam followed by danshen tablets (four tablets orally, three times a day) for 14 days. On the last day of the study they received four danshen tablets with a 15 mg midazolam tablet and plasma concentrations of midazolam and its corresponding metabolite 1-hydroxylmidazolam were measured prior to and after the administration of danshen tablets periodically for 12 h. RESULTS The 90% confidence intervals of C(max,)t(1/2), CL/F and AUC(0,infinity) of midazolam before and after administration of danshen tablets were (0.559, 0.849), (0.908, 1.142), (1.086, 1.688) and (0.592, 0.921), respectively; and those of C-max, t(1/2) and AUC(0,infinity) of 1-hydroxylmidazolam after vs. before administration of danshen tablets were (0.633, 0.923), (0.801, 1.210) and (0.573, 0.980), respectively. Ratios of geometric LS means of C-max(1OHMid) : C-max(Mid) and AUC(max(1OHMid)) : AUC(max(Mid)) (after vs. before 14-day danshen) were 1.072 and 1.035, respectively. CONCLUSIONS Our findings suggest that multiple dose administration of danshen tablets may induce CYP3A4 in the gut. Accordingly, caution should be taken when danshen products are used in combination with therapeutic drugs metabolized by CYP3A.
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