title: Pharmacokinetics of gefitinib in humans: the influence of gastrointestinal factors.
abstract: OBJECTIVE
  To investigate whether differences in plasma pharmacokinetic profiles of gefitinib between healthy subjects having normal (N; t(1/2)>20h) and altered (A; t(1/2)<20h) 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 250mg gefitinib dispersion preparation (IRESSA AstraZeneca) was administered directly into the stomach. Intestinal fluid samples were withdrawn continuously for 180min post-dose using the Loc-I-Gut catheter positioned in the jejunum.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.
authors.affiliation: Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden.
authors.forename: Ebba
authors.initials: E
authors.lastname: Bergman
authors.forename: Patrik
authors.initials: P
authors.lastname: Forsell
authors.forename: Eva M
authors.initials: EM
authors.lastname: Persson
authors.forename: Lars
authors.initials: L
authors.lastname: Knutson
authors.forename: Paul
authors.initials: P
authors.lastname: Dickinson
authors.forename: Robert
authors.initials: R
authors.lastname: Smith
authors.forename: Helen
authors.initials: H
authors.lastname: Swaisland
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Farmer
authors.forename: Mireille V
authors.initials: MV
authors.lastname: Cantarini
authors.forename: Hans
authors.initials: H
authors.lastname: Lennernäs
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011232:Chemical Precipitation; D003460:Crystallization; D005746:Gastric Emptying / Q000502:physiology*; D000077156:Gefitinib; D006207:Half-Life; D006801:Humans; D007419:Intestinal Secretions / Q000378:metabolism; D007441:Intubation, Gastrointestinal; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D008853:Microscopy / Q000379:methods; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D012016:Reference Values; D012995:Solubility; D013059:Spectrum Analysis, Raman
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077156:Gefitinib