Evidence for dissolution rate-limited absorption of COL-3, a matrix metalloproteinase inhibitor,leading to the irregular absorption profile in rats after oral administration |
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Authors: | Li Jing Huynh Hung Chan Eli |
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Affiliation: | (1) Department of Pharmacy, National University of Singapore, Singapore, 117543, Republic of Singapore;(2) Laboratory of Molecular Endocrinology, National Cancer Centre, Singapore, 169610, Republic of Singapore |
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Abstract: | Purpose. 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. |
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Keywords: | COL-3 matrix metalloproteinase inhibitor irregular absorption double- or plateau-peak phenomenon dissolution rate-limited absorption flip-flop situation |
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