Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis
Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis
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DOI：
10.1016/j.clpt.2006.07.004
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发表时间：
2006-10-01
影响因子：
6.7
通讯作者：
Takaoka, Kunio
中科院分区：
文献类型：
--
作者：
Kaneshiro, Yasunori;Oda, Yutaka;Takaoka, Kunio
背景：股骨头坏死（ONFH）是皮质类固醇治疗的主要副作用之一。由于皮质类固醇是由肝细胞色素P450（CYP 3A）代谢的，这种酶的低内源性活性可能有助于ONFH的发病机制。本研究的目的是探讨肝细胞色素P450 3A活性与激素治疗的ONFH易感性之间的关系。在这项前瞻性对照研究中，我们测量了接受骨科手术的类固醇诱导ONFH患者（n = 26）、酒精相关ONFH患者（n = 29）和非ONFH对照患者（n = 75）静脉注射咪达唑仑（0.25 mg/kg）的清除率，以估计肝脏CYP 3A活性。比较各组间咪达唑仑的清除率，并通过多因素分析评估肝脏CYP 3A活性水平与ONFH患病率之间的关系。激素性ONFH患者的咪达唑仑清除率显著低于对照组和酒精相关性ONFH患者（7.7 +/- 1.8 mL中心点kg（-1）中心点min（-1）对比11.4 +/- 3.5 mL中心点kg（-1）中心点min（-1）和10.5 +/- 2.8 mL中心点kg（-1）中心点min（-1）; P <0.001）。咪达唑仑清除率低的患者（< 9.5 mL中心点kg（-1）中心点min（-1））发生激素诱导的ONFH的风险高9倍（校正比值比，9.08 [95%可信区间，2.79-29.6]; P <0.001）。咪达唑仑清除率与酒精相关ONFH的患病率无显著相关性。肝脏CYP 3A活性低可能显著增加类固醇诱导的ONFH的风险。
Background: Osteonecrosis of the femoral head (ONFH) is one of the major side effects of corticosteroid therapy. Because corticosteroids are metabolized by hepatic cytochrome P450 (CYP) 3A, a low endogenous activity of this enzyme may contribute to the pathogenesis of ONFH. The purpose of this study was to examine the possible association of hepatic CYP3A activity and the susceptibility to ONFH in patients treated with corticosteroids.Methods. In this prospective controlled study we measured the clearance of intravenous midazolam (0.25 mg/kg) to estimate hepatic CYP3A activity in patients with steroid-induced ONFH (n = 26), patients with alcohol-related ONFH (n = 29), and non-ONFH control patients (n = 75) undergoing orthopedic surgery. Midazolam clearance was compared between the groups, and the relationship between the level of hepatic CYP3A activity and the prevalence of ONFH was evaluated by multivariate analysis.Results: Midazolam clearance in patients with steroid-induced ONFH was significantly lower than that in control patients and patients with alcohol-related ONFH (7.7 +/- 1.8 mL center dot kg(-1) center dot min(-1) versus 11.4 +/- 3.5 mL center dot kg(-1) center dot min(-1) and 10.5 +/- 2.8 mL center dot kg(-1) center dot min(-1), respectively; P < .001). Patients with low midazolam clearance (< 9.5 mL center dot kg(-1) center dot min(-1)) had a 9-fold greater risk for steroid-induced ONFH (adjusted odds ratio, 9.08 [95% confidence interval, 2.79-29.6]; P < .001). Midazolam clearance did not show a significant correlation with the prevalence of alcohol-related ONFH.Conclusions. Low hepatic CYP3A activity may significantly contribute to the risk for steroid-induced ONFH.