Estimating oral drug absorption in humans.

Abstract

A physical absorption model has been developed using a microscopic mass balance. This model can be used to estimate the extent and rate of oral absorption for compounds absorbed by carrier-mediated as well as passive absorption mechanisms. Using wall permeability parameters of aminopenicillins measured in rats, competitive drug-drug interactions during oral absorption were estimated with regard to the fraction dose absorbed (F) and absorption rate constant. Wall permeabilities of several $\beta$-lactam antibiotics were determined by single-pass perfusion experiments in rats. Ampicillin, amoxicillin, cyclacillin, and cefixime were shown to be absorbed by a carrier-mediated absorption mechanism, from results that showed concentration-dependent permeabilities and competitive inhibition. Our results have suggested that an $\alpha$-amino group on the side chain may be sufficient but not necessary for the absorption of $\beta$-lactam antibiotics via the peptide transporter. The fraction dose absorbed of suspensions of poorly soluble drugs was estimated using a microscopic mass balance approach. There are four underlying dimensionless parameters controlling F: absorption number (An), dose number (Do), dissolution number (Dn), and initial saturation (Is). Is is the drug concentration at the beginning of the intestine. An is the ratio of radial absorption rate to axial convection rate. Do is the ratio of dose concentration to solubility of a drug. Dn is the ratio of residence time in the intestine to dissolution time from particles. Solubility at the physiological pH should be used for calculating Do and Dn of weakly acidic or basic drugs. It was found that F increases with increasing Is, An and Dn, and with decreasing Do. F can be limited by An, Do, or Dn. These parameters should be considered when investigating the bioavailability of a new drug. The effect of micronization on F from suspensions was investigated in terms of Dn. About 90% of maximal F may be achieved at Dn $\approx$ 2. Complete drug absorption can be achieved for drugs with low Do and low Dn by reducing the particle size, whereas drugs with high Do and low Dn may also require a higher solubility to enhance F.