Dog colonoscopy model for predicting human colon absorption.
OBJECTIVE
This study was conducted to develop and validate a dog colon model that predicts colon permeability in humans.


METHODS
The following compounds were studied: Class 1 highly soluble (HS)/highly permeable (HP): aminophylline, propranolol, CP-409092; Class 2 LS/HP: nifedipine; trovafloxacin, sertraline; Class 3 HS/LP: azithromycin, atenolol, CP-331684, CP-424391; Class 4 LS/LP: CJ-13610. Administration to dogs was made 30 cm cranial to the anal sphincter with a lubricated Schott Model VFS-5 flexible endoscope. The bioavailability of the compound following the colon administration in dogs, relative to the same formulation administered orally (relative bioavailability), was determined.


RESULTS
Except for atenolol, a small hydrophillic molecule, the relative bioavailability from administration to the colon of the dog correlated well with the following compound properties: high solubility and high, passive permeability > high solubility, low permeability > low solubility, high, passive permeability approximately low solubility, low permeability.


CONCLUSIONS
The dog colon model is proposed as a surrogate for human intubation studies when the controlled release candidate falls in BCS Classes 2 (LS/HP), 3 (HS/LP), and 4 (LS/LP). However, no human intubation or dog colon studies are required for Class 1 (HS/HP), as these compounds are likely to be well absorbed from the colon.
Sutton
Steven C
SC
BioPharmaceutics Group, Pharmaceutical R&D Department, Pfizer Global R&D, Groton, Connecticut 06357, USA. steven.c.sutton@pfizer.com
Evans
Loreen A
LA
Fortner
Jay H
JH
McCarthy
Jennifer M
JM
Sweeney
Kathy
K
D000284:Administration, Oral; D000285:Administration, Rectal; D000628:Aminophylline / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001262:Atenolol / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D003113:Colonoscopy; D003692:Delayed-Action Preparations; D004285:Dogs; D005772:Gastrointestinal Transit; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D023421:Models, Animal; D008954:Models, Biological; D009543:Nifedipine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010539:Permeability; D012995:Solubility; D013440:Sulfides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
C496810:CJ 13610; D003692:Delayed-Action Preparations; D007093:Imidazoles; D013440:Sulfides; D000628:Aminophylline; D001262:Atenolol; D009543:Nifedipine