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塞来昔布在体外是一种CYP1A2抑制剂,但在体内则不是。

Celecoxib is a CYP1A2 inhibitor in vitro but not in vivo.

作者信息

Karjalainen Marjo J, Neuvonen Pertti J, Backman Janne T

机构信息

Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.

出版信息

Eur J Clin Pharmacol. 2008 May;64(5):511-9. doi: 10.1007/s00228-007-0456-4. Epub 2008 Jan 16.

DOI:10.1007/s00228-007-0456-4
PMID:18197403
Abstract

BACKGROUND AND OBJECTIVE

We recently discovered that rofecoxib is a potent mechanism-based inhibitor of CYP1A2. The effect of the widely used cyclo-oxygenase-2 selective non-steroidal anti-inflammatory drug celecoxib on CYP1A2 activity has not been reported.

METHODS

The effect of celecoxib on CYP1A2 activity (phenacetin O-deethylation) was first studied in vitro using human liver microsomes. This was followed by a randomized, placebo-controlled, cross-over study in which 12 healthy volunteers were given celecoxib (200 mg twice daily) or placebo for 4 days. On day 3, a caffeine test was performed. On day 4, the subjects ingested 2 mg tizanidine. Plasma samples for the measurement of the concentrations of tizanidine, its metabolites and celecoxib were collected up to 24 h post-administration. Pharmacodynamic variables (e.g. blood pressure, subjective drowsiness and drug effect) were recorded up to 12 h post-adm.

RESULTS

Celecoxib was found to be a moderately potent competitive inhibitor of CYP1A2 in vitro with a K(i) (inhibitor constant) of 25.4 microM. However, in vivo, celecoxib did not affect the caffeine test, or the peak concentration, time to peak concentration, area under the concentration-time curve or half-life of tizanidine. The pharmacodynamic variables of tizanidine also remained unchanged.

CONCLUSIONS

Unlike rofecoxib, celecoxib does not clinically to significantly inhibit CYP1A2. The lack of significant in vivo inhibition of CYP1A2 can be correctly predicted on the basis of in vitro K(i) data and the free peripheral or portal plasma concentration of celecoxib.

摘要

背景与目的

我们最近发现罗非昔布是一种强效的基于机制的CYP1A2抑制剂。广泛使用的环氧化酶-2选择性非甾体抗炎药塞来昔布对CYP1A2活性的影响尚未见报道。

方法

首先在体外使用人肝微粒体研究塞来昔布对CYP1A2活性(非那西丁O-脱乙基作用)的影响。随后进行一项随机、安慰剂对照、交叉研究,12名健康志愿者接受塞来昔布(每日两次,每次200 mg)或安慰剂,为期4天。在第3天进行咖啡因试验。在第4天,受试者服用2 mg替扎尼定。在给药后24小时内收集血浆样本,用于测定替扎尼定及其代谢产物和塞来昔布的浓度。记录给药后12小时内的药效学变量(如血压、主观嗜睡和药物效应)。

结果

发现塞来昔布在体外是一种中等强度的CYP1A2竞争性抑制剂,抑制常数(K(i))为25.4 μM。然而,在体内,塞来昔布并不影响咖啡因试验,也不影响替扎尼定的峰浓度、达峰时间、浓度-时间曲线下面积或半衰期。替扎尼定的药效学变量也保持不变。

结论

与罗非昔布不同,塞来昔布在临床上不会显著抑制CYP1A2。根据体外K(i)数据以及塞来昔布的外周或门静脉血浆游离浓度,可以正确预测其在体内对CYP1A2缺乏显著抑制作用。

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Eur J Clin Pharmacol. 2008 Jan;64(1):17-24. doi: 10.1007/s00228-007-0389-y. Epub 2007 Oct 23.
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Covalent binding of rofecoxib, but not other cyclooxygenase-2 inhibitors, to allysine aldehyde in elastin of human aorta.
Drug Metab Dispos. 2007 Oct;35(10):1846-52. doi: 10.1124/dmd.107.016121. Epub 2007 Jul 9.
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Tolfenamic acid is a potent CYP1A2 inhibitor in vitro but does not interact in vivo: correction for protein binding is needed for data interpretation.托芬那酸在体外是一种强效的CYP1A2抑制剂,但在体内并无相互作用:数据解读时需要校正蛋白结合率。
Molecules. 2013 Nov 25;18(12):14470-95. doi: 10.3390/molecules181214470.
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Review: risk for cardiovascular events is increased with rofecoxib, diclofenac, and indomethacin but not celecoxib.
ACP J Club. 2007 Jan-Feb;146(1):24.
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Br J Clin Pharmacol. 2006 Sep;62(3):345-57. doi: 10.1111/j.1365-2125.2006.02653.x.
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