Pharmacokinetics of gefitinib in humans: The influence of gastrointestinal factors

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• 作者：Ebba Bergman ; Patrik Forsell ; Eva M. Persson ; Lars Knutson ; Paul Dickinson ; Robert Smith ; Helen Swaisl ; Matthew R. Farmer ; Mireille V. Cantarini ; Hans Lennernä ; s
• 关键词：Dissolution ; Drug absorption ; Gastric emptying ; Gefitinib ; Intestinal perfusion
• 刊名：International Journal of Pharmaceutics
• 出版年：2007
• 期刊代码：24_03785173
• 类别：pha
• 出版时间：16 August 2007
• 卷：341
• 期：1-2
• 页码：134-142
• 文件大小：306 K

摘要

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.

class="h4">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^®, 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 Intestinal fluid samples were withdrawn continuously for 180 min post-dose using the Loc-I-Gut catheter positioned in the jejunum.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.

class="h4">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.

class="h4">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.