Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping
Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping
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DOI：
10.1067/mcp.2002.129068
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发表时间：
2002-12-01
影响因子：
6.7
通讯作者：
Frye, RF
中科院分区：
文献类型：
--
作者：
Lee, JI;Chaves-Gnecco, D;Frye, RF
目的：测定肝和肠细胞色素P450（CYP）3A活性非常重要，因为由于肝和肠代谢的变化，CYP 3A底物的血浆浓度存在显著差异。本研究的目的是（1）确定肝和肠的提取率是否与分开给药相比，半同时给药后测定的CYP 3A探针药物咪达唑仑的ERH和ERG不同（传统方法），（2）用半同步法研究了酮康唑存在和不存在时咪达唑仑的肝、肠代谢。咪达唑仑药代动力学;在12名健康志愿者中，口服咪达唑仑5 mg，然后在6小时内静脉输注咪达唑仑2 mg。通过非线性回归（半同时法）将浓度-时间数据拟合至经口-静脉输注联合模型。将半同步方法的数据与单独咪达唑仑给药后获得的数据进行比较，间隔1周（传统方法）。同时测定了4名健康志愿者半同时服用酮康唑对咪达唑仑药代动力学的影响。传统和半同步方法之间的生物利用度（0.343+/-0.100 vs 0.343+/-0.094）、ERH（0.269+/-0.064 vs 0.267+/-0.077）和ERG（0.534+/-0.135 vs 0.531+/-0.124）无显著差异。正如预期的那样，酮康唑显着增加的平均生物利用度为0.838（2.4倍），平均ERH下降3.7倍，平均ERG下降5.7倍。结论：咪达唑仑的药代动力学参数，是特定的肝脏和肠道代谢之间的传统和半同步的方法没有什么不同。由于酮康唑的抑制作用，半同时方法也产生了预期的参数显着变化。因此，半同时咪达唑仑法似乎是测定基线和酶抑制时肝和肠CYP 3A活性的合适方法。
Objectives: Determination of hepatic and intestinal cytochrome P450 (CYP) 3A activity is important, because CYP3A substrates show substantial variability in plasma concentrations as a result of variations in both hepatic and intestinal metabolism. The goals of this study were (1) to determine whether the hepatic and intestinal extraction ratios (ERH and ERG, respectively) of the CYP3A probe drug midazolam are different when determined after semisimultaneous administration, as compared with administration on separate occasions (traditional method), and (2) to evaluate the hepatic and intestinal metabolism of midazolam in the presence and absence of ketoconazole by the semisimultaneous method.Methods: Midazolam pharmacokinetics; was assessed in 12 healthy volunteers after administration of midazolam, 5 mg orally, followed at 6 hours by 2 mg given by intravenous infusion. Concentration-time data were fitted to a combined oral-intravenous infusion model by nonlinear regression (semisimultaneous method). Data from the semisimultaneous method were compared with those obtained after individual midazolam doses, 1 week apart (traditional approach). The effect of ketoconazole on midazolam pharmacokinetics after semisimultaneous administration was also determined in 4 healthy volunteers.Results. There were no significant differences in bioavailability (0.343+/-0.100 versus 0.343+/-0.094), ERH (0.269+/-0.064 versus 0.267+/-0.077), and ERG (0.534+/-0.135 versus 0.531+/-0.124) between the traditional and semisimultaneous methods. As expected, ketoconazole markedly increased the mean bioavailability to 0.838 (2.4-fold), the mean ERH was decreased 3.7-fold, and the mean ERG was decreased 5.7-fold.Conclusions: Midazolam pharmacokinetic parameters that are specific to liver and intestinal metabolism were not different between the traditional and semisimultaneous methods. The semisimultaneous method also yielded expected marked changes in the parameters as a result of ketoconazole inhibition. Thus the semisimultaneous midazolam method appears to be a suitable approach to determine hepatic and intestinal CYP3A activity at baseline and with enzyme inhibition.