Predicting oral drug absorption in man for compounds absorbed by carrier mediated and passive absorption processes.

Abstract

Predicting drug absorption and drug absorption variation can considerably aid the selection of c and idates in the drug discovery process as well as identify ways to optimize oral drug delivery in patients. An approach to estimating the fraction dose absorbed in humans is developed based on a macroscopic mass balance analysis. The analysis utilizes membrane absorption parameters, calculated from intestinal perfusion experiments in rats, for drugs absorbed by both carrier mediated and passive adsorption mechanisms. The analysis suggests that the absorption number, An, and the dose to solubility ratio, 1/S$\\sp*$, are key parameters for predicting drug absorption where An = P$\\sp*\\sb{\\rm e}$Gz, P$\\sp*\\sb{\\rm e}$ is the dimensionless effective permeability, and Gz is the Graetz number. Three equations predicting fraction absorbed are developed for the following cases of drug in solution: drug concentration (1) below the solubility, (2) initially exceeding the solubility, and (3) always greater than the solubility. Model compounds used for the correlations included those absorbed by carrier mediated and /or passive absorption processes. Literature values for intestinal wall permeability are used for the passively absorbed compounds whereas the absorption parameters for the carrier mediated compounds were determined from intestinal perfusion experiments in rats. Human fraction dose absorbed (F) data and An showed an excellent correlation. The theoretical analysis, confirmed by experimental results, demonstrates that two of the fundamental parameters controlling drug absorption are the absorption number and the dose to solubility ratio. The $\\beta$-lactam antibiotic intestinal absorption mechanism is characterized using single pass perfusion technique in rats. The membrane absorption parameters, J$\\sp*\\sb{\\rm max}$(maximal flux), K$\\sb{\\rm m}$(Michaelis Constant), and P$\\sp*\\sb{\\rm c}$(carrier permeability) for amoxicillin, cephalexin, cephradine, cefatrizine, cefaclor, and cefadroxil were determined. Analysis of the data using a modified boundary layer method revealed nonpassive membrane transport. Competitive absorption studies performed with $\\beta$-lactam antibiotics, amino acids, and several small peptides suggest that absorption interactions between carrier mediated compounds, including other drugs, peptides or amino acids, may be clinically significant and may account for a second possible mechanism along with delayed gastric emptying for the delay in antibiotic plasma levels.Ph.D.Pharmaceutical sciencesUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/161975/1/8821654.pd