健康志愿者中咪达唑仑和利多卡因药代动力学与MEGX形成之间的相关性。
Correlation between midazolam and lignocaine pharmacokinetics and MEGX formation in healthy volunteers.
作者信息
Swart Eleonora L, van der Hoven Ben, Groeneveld A B Johan, Touw Daniel J, Danhof Meindert
机构信息
Department of Pharmacy and Medical Intensive Care Unit, University Hospital Vrije Universiteit, PO Box 7057, 1007 MB Amsterdam, the Netherlands.
出版信息
Br J Clin Pharmacol. 2002 Feb;53(2):133-9. doi: 10.1046/j.0306-5251.2001.01182.x.
AIMS
The objectives of the present investigation were: (a) to determine the correlation between lignocaine and midazolam pharmacokinetics following intravenous administration in healthy volunteers, (b) to determine the effects of treatment with an inhibitor of CYP3A4 (erythromycin) on this correlation and (c) to assess the precision of the MEGX-test as a sole predictor of lignocaine and midazolam pharmacokinetics.
METHODS
The study was conducted in four male and four female healthy volunteers, aged between 21 and 26 years, who received 1 mg kg-1 lignocaine HCl i.v. on days 1, 3, 5, 9 and 10 of the investigation. On days 5 and 10 they also received midazolam, 0.075 mg kg-1 i.v. and from days 6-10 they took erythromycin 500 mg orally, four times daily. Following administration of lignocaine and midazolam, frequent venous blood samples were obtained for determination of the concentrations of lignocaine, MEGX and midazolam.
RESULTS
In the absence of erythromycin a statistically significant linear correlation was observed between the clearance of lignocaine and midazolam (CL(midazolam)= 0.41 x CL(lignocaine)+ 1.2; r(2) = 0.857; P < 0.001). Erythromycin cotreatment resulted in a loss of the correlation between the two clearances (r(2) = 0.39; P = 0.1). Erythromycin caused a statistically significant reduction in midazolam clearance from the original value of 3.8 to 2.5 (95% CI for the difference -2.27, -0.35) ml kg-1 min-1. Interestingly there was no significant change in the clearance of lignocaine (6.4 vs 5.8 (95% CI for the difference -2.74, -1.51) ml kg-1 min-1). Furthermore no correlation at all was observed between the MEGX-test and lignocaine or midazolam clearances. Considering the data on day 1, 3 and 5 the intra-individual coefficient of variation in the MEGX-test was 45.3% at 15 min and 23.5% at 30 min, respectively.
CONCLUSIONS
It is concluded that there is a significant correlation between lignocaine and midazolam clearances but this correlation is lost after CYP3A4 inhibition by erythromycin. The MEGX-test is of no value in assessing intra- and inter-individual variability in midazolam clearance.
目的
本研究的目的为：(a) 确定健康志愿者静脉注射利多卡因和咪达唑仑后二者药代动力学之间的相关性；(b) 确定用细胞色素P450 3A4（CYP3A4）抑制剂（红霉素）治疗对这种相关性的影响；(c) 评估MEGX试验作为利多卡因和咪达唑仑药代动力学唯一预测指标的准确性。
方法
研究纳入4名年龄在21至26岁之间的男性和4名女性健康志愿者，在研究的第1、3、5、9和10天静脉注射1 mg/kg盐酸利多卡因。在第5和10天，他们还静脉注射0.075 mg/kg咪达唑仑，从第6至10天，他们口服500 mg红霉素，每日4次。静脉注射利多卡因和咪达唑仑后，频繁采集静脉血样，以测定利多卡因、MEGX和咪达唑仑的浓度。
结果
在未使用红霉素的情况下，观察到利多卡因清除率与咪达唑仑清除率之间存在统计学上显著的线性相关性（CL(咪达唑仑)= 0.41×CL(利多卡因)+ 1.2；r² = 0.857；P < 0.001）。联合使用红霉素导致两种清除率之间的相关性消失（r² = 0.39；P = 0.1）。红霉素使咪达唑仑清除率从初始值3.8显著降低至2.5（差异的95%可信区间为-2.27，-0.35）ml·kg⁻¹·min⁻¹。有趣的是，利多卡因清除率没有显著变化（6.4对5.8（差异的95%可信区间为-2.74，-1.51）ml·kg⁻¹·min⁻¹）。此外，未观察到MEGX试验与利多卡因或咪达唑仑清除率之间存在任何相关性。考虑第1、3和5天的数据，MEGX试验在15分钟时个体内变异系数为45.3%，在30分钟时为23.5%。
结论
得出结论，利多卡因和咪达唑仑清除率之间存在显著相关性，但在红霉素抑制CYP3A4后这种相关性消失。MEGX试验在评估咪达唑仑清除率的个体内和个体间变异性方面没有价值。
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