Pharmacokinetics of gefitinib in humans: the influence of gastrointestinal factors.
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 Intestinal fluid samples were withdrawn continuously for 180min post-dose using the Loc-I-Gut catheter positioned in the jejunum.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.
Bergman
Ebba
E
Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden.
Forsell
Patrik
P
Persson
Eva M
EM
Knutson
Lars
L
Dickinson
Paul
P
Smith
Robert
R
Swaisland
Helen
H
Farmer
Matthew R
MR
Cantarini
Mireille V
MV
Lennernäs
Hans
H
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
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077156:Gefitinib