利福平与利奈唑胺联合给药对利奈唑胺药代动力学的影响：临床及动物研究
Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies.
作者信息
Hashimoto Satsuki, Honda Kyoko, Fujita Kohei, Miyachi Yuka, Isoda Kazuya, Misaka Ko, Suga Yukio, Kato Satoshi, Tsuchiya Hiroyuki, Kato Yukio, Okajima Masaki, Taniguchi Takumi, Shimada Tsutomu, Sai Yoshimichi
机构信息
1Department of Hospital Pharmacy, University Hospital, Kanazawa University, 13-1, Takara-machi, Kanazawa, Ishikawa 920-8641 Japan.
2Department of Medicinal Informatics, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takara-machi, Kanazawa, Ishikawa 920-8641 Japan.
出版信息
J Pharm Health Care Sci. 2018 Nov 12;4:27. doi: 10.1186/s40780-018-0123-1. eCollection 2018.
BACKGROUND
Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. However, the mechanism of the drug-drug interaction between LZD and RFP is unknown.
METHODS
We conducted a prospective, open-label, uncontrolled clinical study in Japanese patients receiving LZD and RFP to evaluate the effect of coadministered RFP on the concentration of LZD. In animal study in rats, the influence of coadministered RFP on the pharmacokinetics of LZD administered intravenously or orally was examined. Intestinal permeability was investigated with an Ussing chamber to assess whether coadministered RFP alters the absorption process of LZD in the intestine.
RESULTS
Our clinical study indicated that multiple doses of RFP reduced the dose-normalized trough concentration of LZD at the first assessment day by an average of 65%. In an animal study, we found that multiple doses of RFP significantly decreased the area under the concentration-time curve, the maximum concentration and the bioavailability of orally administered LZD by 48%, 54% and 48%, respectively. In contrast, the pharmacokinetics of intravenously administered LZD was unaffected by the RFP pretreatment. However, investigation of the intestinal permeability of LZD revealed no difference in absorptive or secretory transport of LZD in the upper, middle and lower intestinal tissues between RFP-pretreated and control rats, even though RFP induced gene expression of multidrug resistance protein 1a and multidrug resistance-associated protein 2.
CONCLUSIONS
Therapeutic drug monitoring may be important for avoiding subtherapeutic levels of LZD in the combination therapy. The drug-drug interaction between LZD and RFP may occur only after oral administration of LZD, but is not due to any change of intestinal permeability of LZD.
TRIAL REGISTRATION
UMIN, UMIN000004322. Registered 4 October 2010.
背景
利奈唑胺（LZD）与利福平（RFP）联合治疗革兰氏阳性菌感染可能比单一疗法更有效，但多项研究表明，RFP会降低LZD的血药浓度，从而增加治疗失败和出现LZD耐药菌株的风险。然而，LZD与RFP之间药物相互作用的机制尚不清楚。
方法
我们对接受LZD和RFP治疗的日本患者进行了一项前瞻性、开放标签、非对照临床研究，以评估联合使用RFP对LZD浓度的影响。在大鼠动物研究中，研究了联合使用RFP对静脉注射或口服LZD药代动力学的影响。使用尤斯灌流小室研究肠道通透性，以评估联合使用RFP是否会改变LZD在肠道的吸收过程。
结果
我们的临床研究表明，多次服用RFP后，在首次评估日，LZD的剂量标准化谷浓度平均降低了65%。在动物研究中，我们发现多次服用RFP可使口服LZD的浓度-时间曲线下面积、最大浓度和生物利用度分别显著降低48%、54%和48%。相比之下，静脉注射LZD的药代动力学不受RFP预处理的影响。然而，对LZD肠道通透性的研究表明，即使RFP诱导了多药耐药蛋白1a和多药耐药相关蛋白2的基因表达，在RFP预处理大鼠和对照大鼠的上、中、下肠道组织中，LZD的吸收或分泌转运也没有差异。
结论
治疗药物监测对于避免联合治疗中LZD出现亚治疗水平可能很重要。LZD与RFP之间的药物相互作用可能仅在口服LZD后发生，但并非由于LZD肠道通透性的任何变化所致。
试验注册
UMIN，UMIN000004322。2010年10月4日注册。
Zotero 插件