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首页> 外文学位 >Interindividual variations in drug metabolism: Implications for predicting clinically important drug interactions.
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Interindividual variations in drug metabolism: Implications for predicting clinically important drug interactions.

机译：个体间药物代谢差异：预测临床上重要的药物相互作用的意义。

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摘要

Interindividual differences in drug metabolism may be an important factor determining drug interactions. One goal of this thesis was to compare the effects of the CYP3A4 inhibitors, ketoconazole (KTC), erythromycin (ERM) and grapefruit juice (GFJ), on the pharmacokinetics and pharmacodynamics of the antiarrhythmic drug, propafenone. It is normally extensively metabolized by cytochrome P450 2136 (CYP2D6), an enzyme that shows genetic polymorphism, and moderately metabolized by CYP3A4 and CYPIA2. The first study assessed the interaction in 12 subjects with different CYP2D6 activity. Subjects with high CYP2D6 activity (n = 9) had low plasma peak propafenone concentration (Cmax, 0.09 ± 0.03 μg/mL, mean ± SD) and area under the curve (AUC, 0.28 ± 0.15 μg.h/mL, mean ± SD) with water (control). These parameters were not altered by any CYP3A4 inhibitor. Subjects with low CYP2D6 activity (n = 3) had high propafenone Cmax (0.82 ± 0.24) and AUC (7.59 ± 4.87) with water. These parameters were further increased by KTC (1.36 ± 0.07, 13.10 ± 4.91; p 0.01), ERM (1.24 ± 0.54, 10.09 ± 4.13, p 0.05) and GFJ (1.06 ± 0.36, 10.13 ± 3.87, p 0.05) suggesting that the interaction was relevant to individuals with low CYP2D6 activity.; In a follow-up study, 114 subjects were screened for CYP2D6 activity and six CYP2D6 poor metabolizers (PM) were tested. Propafenone Cmax and AUC with water (0.96 ± 0.30; 11.01 ± 3.22) were increased by KTC (1.90 ± 0.60; 23.60 ± 6.70, p 0.001), ERM (1.30 ± 0.30; 16.50 ± 5.10, p 0.05) and GFJ (1.50 ± 0.60; 16.10 ± 4.50, p 0.05). There were no significant changes in electrocardiogram recordings in CYP2D6 PM with CYP3A4 inhibitors.; A third study compared the effects of 4 week administration of GFJ or orange juice (OJ, control) on the activity of warfarin (International Normalized Ratio, INR) in 23 patients undergoing stable anticoagulation therapy. Warfarin is primarily metabolized by CYP2C9, which exhibits genetic polymorphism, and by several other CYP450 enzymes including CYP3A4. There was no difference in mean warfarin dose/INR ratio between treatments assessed weekly. No individual had consistently lower warfarin dose/INR ratio with GFJ compared to OJ.; Significant pharmacokinetic drug interactions can occur between propafenone and CYP3A4 inhibitors depending on CYP2D6 activity. These studies suggest the importance of knowing the phenotype/genotype of patients in order to prevent drug interactions.
机译：个体间的药物代谢差异可能是决定药物相互作用的重要因素。本论文的一个目标是比较CYP3A4抑制剂，酮康唑（KTC），红霉素（ERM）和葡萄柚汁（GFJ）对抗心律不齐药物普罗帕酮的药代动力学和药效学的影响。它通常被细胞色素P450 2136（CYP2D6）广泛代谢，该酶显示出遗传多态性，并被CYP3A4和CYPIA2中等程度地代谢。第一项研究评估了12位具有不同CYP2D6活性的受试者的相互作用。 CYP2D6活性高的受试者（n = 9）血浆普罗帕酮血浆峰浓度低（Cmax，0.09±0.03μg/ mL，平均值±SD）和曲线下面积（AUC，0.28±0.15μg.h/ mL，平均值±SD ）用水（对照）。这些参数没有被任何CYP3A4抑制剂改变。 CYP2D6活性低的受试者（n = 3）用水中普罗帕酮Cmax（0.82±0.24）和AUC（7.59±4.87）高。 KTC（1.36±0.07，13.10±4.91; p <0.01），ERM（1.24±0.54，10.09±4.13，p <0.05）和GFJ（1.06±0.36，10.13±3.87，p <0.05）进一步提高了这些参数提示该相互作用与CYP2D6活性低的个体有关。在后续研究中，对114名受试者的CYP2D6活性进行了筛查，并测试了6种CYP2D6弱代谢者（PM）。 KTC（1.90±0.60; 23.60±6.70，p <0.001），ERM（1.30±0.30; 16.50±5.10，p <0.05）和GFJ（普罗帕酮Cmax和AUC用水（0.96±0.30; 11.01±3.22）增加1.50±0.60; 16.10±4.50，p <0.05）。使用CYP3A4抑制剂的CYP2D6 PM心电图记录无明显变化。第三项研究比较了接受GFJ或橙汁（OJ，对照）4周对23名接受稳定抗凝治疗的患者中华法林活性的影响（国际标准化比率，INR）。华法林主要由具有遗传多态性的CYP2C9和包括CYP3A4在内的其他几种CYP450酶代谢。每周评估的治疗之间的平均华法林剂量/ INR比没有差异。与OJ相比，没有人持续服用GFJ降低华法林剂量/ INR。取决于CYP2D6的活性，普罗帕酮和CYP3A4抑制剂之间可能发生重要的药代动力学药物相互作用。这些研究表明了解患者表型/基因型的重要性，以防止药物相互作用。

著录项

  • 作者

    Munoz, Claudio Enrique.;

  • 作者单位

    The University of Western Ontario (Canada).;

  • 授予单位 The University of Western Ontario (Canada).;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 111 p.
  • 总页数 111
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

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