Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole
Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole
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DOI：
10.1067/mcp.2002.127397
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发表时间：
2002-10-01
影响因子：
6.7
通讯作者：
Kivistö, KT
中科院分区：
文献类型：
--
作者：
Raaska, K;Niemi, M;Kivistö, KT
目的：我们的目的是研究伊曲康唑的药代动力学和皮质醇抑制活性的布地奈德吸入administered by inhalation.Methods：在一项随机，双盲，2阶段的交叉研究，10名健康受试者服用200毫克伊曲康唑或安慰剂口服5天，每天一次。第5天，伊曲康唑或安慰剂末次给药后1小时，吸入1000 μ g布地奈德。血浆布地奈德和皮质醇浓度测定达23小时。与安慰剂相比，伊曲康唑使吸入布地奈德的平均血药浓度-时间曲线下面积增加4.2倍（范围1.7倍至9.8倍; P <0.01），血药峰浓度增加1.6倍（P <0.01）。伊曲康唑使布地奈德的平均终末半衰期从1.6小时延长至6.2小时（即3.7倍;范围，1.5倍至9.3倍; P <0.001）。与安慰剂相比，吸入布地奈德后伊曲康唑对皮质醇产生的抑制作用显著增强，如血浆皮质醇浓度-时间曲线下面积从0.5至10小时减少43（P <0.001），在布地奈德给药后23小时（上午8点）测量的皮质醇浓度下降12结论：伊曲康唑显著增加吸入布地奈德的全身暴露量，可能是通过抑制细胞色素P4503 A4介导的布地奈德首过和消除相代谢。这种相互作用导致布地奈德的全身效应增强，如皮质醇产生的抑制所示。布地奈德和强效CYP 3A 4抑制剂长期联合给药可能与布地奈德不良反应风险增加相关。
Objective: Our objective was to examine the effects of itraconazole on the pharmacokinetics and cortisol-suppressant activity of budesonide administered by inhalation.Methods: In a randomized, double-blind, 2-phase crossover study, 10 healthy subjects took 200 mg itraconazole or placebo orally once a day for 5 days. On day 5, 1 hour after the last dose of itraconazole or placebo, 1000 mug budesonide was administered by inhalation. Plasma budesonide and cortisol concentrations were measured up to 23 hours.Results. Itraconazole increased the mean total area under the plasma concentration-time curve of inhaled budesonide 4.2-fold (range, 1.7-fold to 9.8-fold; P < .01) and the peak plasma concentration 1.6-fold (P < .01) compared with placebo. The mean terminal half-life of budesonide was prolonged from 1.6 to 6.2 hours (ie 3.7-fold; range, 1.5-fold to 9.3-fold; P < .001) by itraconazole. The suppression of cortisol production after inhalation of budesonide was significantly increased by itraconazole as compared with placebo, as shown by a 43% reduction in the area under the plasma cortisol concentration-time curve from 0.5 to 10 hours (P < .001) and a 12% decrease in the cortisol concentration measured 23 hours after administration of budesonide, at 8 am (P < .05).Conclusions: Itraconazole markedly increased systemic exposure to inhaled budesonide, probably by inhibiting the cytochrome P4503A4-mediated metabolism of budesonide during both the first-pass and the elimination phases. This interaction resulted in enhanced systemic effects of budesonide, as shown by suppression of cortisol production. Long-term coadministration of budesonide and a potent CYP3A4 inhibitor may be associated with an increased risk of adverse effects of budesonide.