Pharmacokinetics of gefitinib in humans:: The influence of gastrointestinal factors
Pharmacokinetics of gefitinib in humans:: The influence of gastrointestinal factors
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DOI：
10.1016/j.ijpharm.2007.04.002
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发表时间：
2007-08-16
影响因子：
5.8
通讯作者：
Lennernaes, Hans
中科院分区：
文献类型：
--
作者：
Bergman, Ebba;Forsell, Patrik;Lennernaes, Hans
目的：探讨吉非替尼在正常(N；t(1/2)和Gt；20h)和异常(A；t(1/2)和lt；20h)药代动力学(PK)曲线正常和(A；t(1/2)和lt；20h)健康受试者之间的差异是否可以通过胃排空和/或吉非替尼在近端小肠的沉淀/溶出的个体差异来解释。方法：对100名健康男性受试者进行筛选，以识别具有两种PK曲线的受试者。来自筛查的25名受试者随后参加了一项插管研究，将250毫克的吉非替尼分散剂(IRESSA(R)，阿斯利康)直接注入胃中。给药后用Loc-I-Gut空肠导管连续抽取肠液样本180min。结果：在胃排空和空肠液中吉非替尼的沉淀/溶出度方面，正常受试者和异常受试者之间均无差异。由于空肠液样品中的结晶难以鉴定，只能鉴定出与给药形式相同的结晶形态。结论：吉非替尼在人空肠近端的胃排空、沉淀和再溶出方面与正常受试者和变异受试者没有显著差异。其他机制(S)也可能是解释吉非替尼血浆暴露的个体差异的重要原因，例如各种代谢酶和/或运输蛋白的多态性。然而，改变的受试者和正常受试者之间的差异很难解释，这可能是一个多因素的解释，包括空肠pH值低，酶和转运蛋白活性的表达增加，以及快速的小肠传输。(C)2007年，爱思唯尔出版。
Purpose: To investigate whether differences in plasma pharmacokinetic profiles of gefitinib between healthy subjects having normal (N; t(1/2) > 20 h) and altered (A; t(1/2) < 20 h) pharmacokinetic (PK) profiles might be explained by inter-individual variability in gastric emptying and/or precipitation/dissolution of gefitinib in the proximal small intestine.Methods: One hundred healthy male subjects were screened to enable identification of subjects with the two PK profiles. Twenty five subjects from the screening were subsequently enrolled in an intubation study where a 250 mg gefitinib dispersion preparation (IRESSA (R), AstraZeneca) was administered directly into the stomach. Intestinal fluid samples were withdrawn continuously for 180 min post-dose using the Loc-I-Gut catheter positioned in the jejunum. The crystalline form of gefitinib was determined using Raman microscopy.Results: There were no differences between normal and altered subjects with regard to gastric emptying or the precipitation/dissolution of gefitinib in jejunal fluid. Due to difficulties in crystalline identification in the jejunal fluid samples, only the same crystalline form as the dosed form was identified.Conclusions: There was no pronounced difference in gastric emptying, precipitation and re-dissolution of gefitinib in proximal human jejunum between normal and altered subjects. Other mechanism(s) are also likely to be important in explaining the inter-individual differences in plasma exposure to gefitinib, such as polymorphism in various metabolic enzymes and/or transport proteins. However, the difference between altered and normal subjects cannot be easily explained and it is likely a multifactorial explanation including low jejunal pH, increased expression of enzymatic and transporter activity and rapid small intestine transit. (c) 2007 Published by Elsevier B.V.