Gastrointestinal Motility Variation and Oral Drug Absorption.

Abstract

Gastrointestinal (GI) motility is a physiological factor that affects oral drug absorption by controlling a drug's residence time in the GI tract. The development of an oral drug absorption model, the pulsatile emptying transit (PET) model, which takes into account variations in GI motility due to the migrating motor complex (MMC) is described. The absorption rate outputted by the PET model can be used as an input for pharmacokinetic models to estimate drug plasma concentration-time profiles. The effect of variations in GI motility on the drug plasma concentration-time profiles of high permeability and high solubility (BCS Class I) drugs was simulated. Simulations showed that increases in the maximum plasma concentration (Cmax) greater than 10% can occur when drugs that have an effective permeability greater than 0.04 cm/min and a high dissolution rate (85% of the dose dissolves within 15 minutes) are dosed during phase III of the MMC. Many explanations have been given for the appearance of double peaks in oral ranitidine plasma concentration-time curves. Using a discontinuous PET model with a 2-compartment pharmacokinetic model, parameter sensitivity analysis was done on the following parameters: dosing time relative to the MMC, dissolution rate, effective permeability in the duodenum and ileum, and intravenous pharmacokinetic parameters (k12, k21, kout, Vd). Simulations suggest that the variety of shapes for ranitidine plasma concentration-time profiles with double peaks is a result of differences in these parameter values between individuals. In addition, simulations showed that the dosing time relative to the MMC coupled with discontinuous absorption sites along the small intestine can explain the absence and presence of double peaks in oral ranitidine plasma concentration-time profiles. Cocrystals are non-covalently bonded crystal complexes with two or more components. The formation of cocrystals offers a means to alter the dissolution rate of a solid without changing covalent bonds. Dissolution experiments with CBZ:NCT cocrystal and CBZ(III) crystal in ethanol, 2-propanol and ethyl acetate were conducted and the relative dissolution rates were compared with estimated relative dissolution rates based on stoichiometric cocrystal solubility. Statistically significant differences in relative dissolution rates were not observed in all three solvents.