INFLUENCE OF COSOLVENTS ON THE ABSORPTIVE CLEARANCE OF KETOTIFEN FUMARATE FROM RABBIT INTESTINE, IN-SITU

Abstract

Objective: Investigate the effect of ethanol, polyethylene glycol 400, propylene glycol, glycerol and sorbitol on the absorptive clearance of ketotifen fumarate   in the rabbit. Methods: In-situ intestinal perfusion technique, through and through was used for estimation of membrane transport parameters of ketotifen fumarate from duodenum, jejunum, ileum and ascending colon in the rabbit. These parameters include absorptive clearance per unit length PeA/L (ml/min.cm), percentage fraction absorbed per unit length (% Fa/cm) and anatomical length that required for complete absorption in specific segment (L95%). Results: The absorption was in the order ascending colon> duodenum > jejunum> ileum; where the absorptive clearance normalized to intestinal segment length PeA/L (ml/min.cm) was 0.0071 ± 0.0003, 0.0058 ± 0.0001, 0.0051 ± 0.0001, and 0.0047 ± 0.0001 in each segment respectively. The effect of cosolvents in jejunum was in the order; ethanol 15% >glycerol 30% > propylene glycol (PG40%) > polyethylene glycol400 (PEG-400 40%) >sorbitol 40%, Where the absorptive clearance normalized to intestinal segment length PeA/L (ml/min.cm), mean ± SE was: 0.0142 ±0.0011, 0.0086 ± 0.0002, 0.0075 ± 0.0003, 0.0022 ± 0.0001, and 0.0014 ± 0.0001 for each cosolvents respectively. The same order was obtained in the ascending colon. Conclusion: The enhancing action of the ethanol, propylene glycol and glycerol may be due fluidization of the cell membrane with a subsequent increase in transcellular absorption, while the inhibitory effect of polyethylene glycol and sorbitol could attributed to water secretion, H-bonding formation and reduced thermodynamic activity of drug molecules.