Comparative assessment of two indices of drug induced permeability changes in the perfused rat intestine.
In the present study, two indices of acute intestinal permeability changes were investigated as measurements of drug induced intestinal damage. The first method was based on 14C-polyethylene glycol (PEG) 4000 permeability assessment and the second was based on histological evaluation of the intestine. The test compounds were ibuprofen, ketoprofen and naproxen and the alanine, glycine and phenylalanine amide derivatives of ibuprofen. Perfusion studies were carried out using a rat model. Post-perfusion, the gut was fixed and tissue changes were assessed and scored. Ibuprofen, ketoprofen and naproxen altered the barrier properties of the intestine to PEG 4000 with significantly higher scores (p<0.05) for gastrointestinal toxicity relative to blank buffer. For ketoprofen, PEG 4000 permeability and intestinal damage scores increased with increasing ketoprofen concentration. Ibuprofen amide derivatives did not induce significant histological damage or PEG 4000 permeability when compared with ibuprofen. A correlation coefficient of 0.91 is obtained when intestinal damage scores are plotted against PEG 4000 permeability for all compounds. Both indices are proposed as rapid and useful measures of drug induced acute intestinal damage.
School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK. majella.lane@tcd.ie
Majella E
ME
Lane
Karl
K
Levis
George S A
GS
McDonald
Owen I
OI
Corrigan
D000409:Alanine / Q000737:chemistry; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics*; D005998:Glycine / Q000737:chemistry; D007052:Ibuprofen / Q000009:adverse effects / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology*; D007660:Ketoprofen / Q000009:adverse effects / Q000493:pharmacokinetics; D009288:Naproxen / Q000009:adverse effects / Q000493:pharmacokinetics; D010539:Permeability; D010649:Phenylalanine / Q000737:chemistry; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011092:Polyethylene Glycols; D010649:Phenylalanine; D009288:Naproxen; D007660:Ketoprofen; D000409:Alanine; D005998:Glycine; D007052:Ibuprofen