title: Evidence for dissolution rate-limited absorption of COL-3, a matrix metalloproteinase inhibitor, leading to the irregular absorption profile in rats after oral administration.
abstract: OBJECTIVE
  This study was undertaken to elucidate the underlying mechanism of the irregular absorption profiles of COL-3, a matrix metalloproteinase inhibitor, with a double- or plateau-peak concentration after a single oral dose administration of COL-3 suspension to rats.
  
  
  METHODS
  The gastrointestinal absorption profiles of COL-3 in rats were assessed by comparing serum drug concentration curves after the following various modes of drug administration: oral and intraduodenal doses, oral doses of COL-3 in fine and coarse suspensions, intraduodenal dosing to the bile-duct intact and cannulated (BDC) rats, and oral doses with and without food. In addition, the biliary excretion of COL-3 in the BDC rats was examined.
  
  
  RESULTS
  Neither variable gastric emptying nor enterohepatic recycling was the source of the irregular gastrointestinal absorption of COL-3 in rats. Reduction in particle size, presence of food and endogenous bile emerged as the determinants of the oral absorption of COL-3 by enhancing the dissolution of the solid drug in the gastrointestinal fluids. Flip-flop of the absorption and elimination rate constants was noted only for COL-3 after intraduodenal administration of the coarse suspension to the BDC rats with the bile flow diverged out of the body.
  
  
  CONCLUSIONS
  Variability in dissolution rate-limited absorption was the main cause of the irregular absorption of COL-3 after oral administration of its solid dosage form.
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore 117543, Republic of Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Hung
authors.initials: H
authors.lastname: Huynh
authors.forename: Eli
authors.initials: E
authors.lastname: Chan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013754:Tetracyclines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013754:Tetracyclines; C117155:tetracycline CMT-3; D020782:Matrix Metalloproteinases