The correlation between CYP3A activity and the risk of osteonecrosis.

CYP3A活性与骨坏死风险之间的相关性。

• 批准号: 17591590
• 负责人: KOBAYASHI Akio
• 金额: $ 2.18万
• 依托单位: Osaka City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591590/
• 关键词: osteonecrosis; CYP3A; グルココルチコイド; CYP3A4; 特発性大腿骨頭壊死症; midazolam clearance

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・kg^<-1>・min^<-1> versus 11.4 ±3.5 mL・kg^<-1>・min^<-1> and 10.5 ± 2.8 mL・kg^<-1>・min^<-1>, respectively; P <.001). Patients with low midazolam clearance (<9.5 mL・kg^<-1>・ 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.

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，该酶的低内源性活性可能与ONFH的发病机制有关。本研究的目的是研究在接受皮质类固醇治疗的患者中，肝脏CYP3A活性与ONFH易感性的可能关联。方法：在这项前瞻性对照研究中，我们测量了静脉注射咪达唑仑（0.25 mg/kg）的清除率，以估计类固醇诱导的ONFH患者（n=26）、酒精相关ONFH患者（n=29）和非ONFH对照患者（n=75）接受骨科手术的肝脏CYP3A活性。比较两组患者咪达唑仑清除率，并通过多因素分析评估肝脏CYP3A活性水平与ONFH患病率的关系。结果：激素性ONFH患者咪达唑仑清除率显著低于对照组和酒精相关性ONFH患者（分别为7.7±1.8 mL·kg^<-1>·min^<-1>和11.4±3.5 mL·kg^<-1>·min^<-1>和10.5±2.8 mL·kg^<-1>·min^<-1>, P < 0.001）。咪达唑仑清除率低（<9.5 mL·kg^<-1>·min^<-1>）的患者发生类固醇诱导ONFH的风险高出9倍（校正优势比）。9.08[95%可信区间，2.79-29.6]；P <措施)。咪达唑仑清除率与酒精相关的ONFH患病率无显著相关性。结论：肝脏CYP3A活性低可能显著增加激素诱导ONFH的风险。

项目成果

Optimized use of a biodegradable polymer as a carrier material for the local delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2)

• DOI: 10.1016/j.biomaterials.2005.10.007
• 发表时间: 2006-03-01
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Kato, M;Toyoda, H;Takaoka, K
• 通讯作者: Takaoka, K

Preparation of the flexion gap affects the extension gap in total knee arthroplasty

• DOI: 10.1016/j.arth.2003.12.085
• 发表时间: 2005-08-01
• 期刊: JOURNAL OF ARTHROPLASTY
• 影响因子: 3.5
• 作者: Sugama, R;Kadoya, Y;Takaoka, K
• 通讯作者: Takaoka, K

Polyethylene wear particle generation in vivo in an alumina medial pivot total knee prosthesis.

氧化铝内侧枢轴全膝关节假体体内聚乙烯磨损颗粒的产生。

• 发表时间: 2005
• 期刊: Biomaterials 26・(30)
• 作者: Minoda Y;Kobayashi A;Iwaki H;Miyaguchi M;Kadoya Y;Ohashi H;Takaoka K.
• 通讯作者: Takaoka K.

Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis

• DOI: 10.1016/j.clpt.2006.07.004
• 发表时间: 2006-10-01
• 期刊: CLINICAL PHARMACOLOGY & THERAPEUTICS
• 影响因子: 6.7
• 作者: Kaneshiro, Yasunori;Oda, Yutaka;Takaoka, Kunio
• 通讯作者: Takaoka, Kunio

A biodegradable delivery system for antibiotics and recombinant human bone morphogenetic protein‐2: A potential treatment for infected bone defects

• DOI: 10.1002/jor.20049
• 发表时间: 2006-03
• 期刊: Journal of Orthopaedic Research
• 影响因子: 2.8
• 作者: A. Suzuki;H. Terai;H. Toyoda;T. Namikawa;Yoshiko Yokota;Takanori Tsunoda;K. Takaoka