Estimating human drug oral absorption kinetics from Caco-2 permeability using an absorptiondisposition model: model development and evaluation and derivation of analytical solutions for k (a) and F (a).
ABSTRACT Intestinal transcellular permeability (P m ), measured across cell lines such as Caco-2 cells in vitro, is often used for assessing oral drug absorption potential in humans. However, the quantitative link between in vitro permeability and apparent in vivo absorption kinetics, based on drug appearance in plasma, is poorly understood. In the current study, a novel absorptiondisposition kinetic model that links traditional pharmacokinetic and mass transfer models was developed. Analytical solutions of k a and F a were deduced, and using Caco-2 permeability, F a in humans was predicted for 51 structurally diverse compounds. Predicted F a values were similar to and correlated highly with their corresponding experimental values with an average error of 1.88 Ϯ 1.06% (Ϫ17 to 22%) and r 2 ϭ 0.934. Simulated concentration profiles for 17 of 18 drugs corresponded to observed plasma concentration profiles in healthy volunteers. The equilibrium solution for k a (k a,eq ) was found to be a key determinant of F a , whereas under sink conditions, k a is likely to be a determinant of plasma concentration kinetics. The current version of the model offers a quantitative approach for predicting human oral absorption kinetics from in vitro permeability. It also establishes, for the first time, a quantitative link between P m and k a and between k a,eq and F a . This will facilitate better in vitro or in situ-in vivo correlations since it establishes a basis for incorporating permeability coefficients from the various experimental formats based on drug loss or appearance that are commonly used in the laboratory for permeability determination. Oral administration is the most commonly used drug-dosing route. Therefore, the ability to predict the rate and extent of absorption of drug candidates after oral administration is crucial during the preclinical phase of development. Such knowledge complements high throughput drug screening and allows scientists to select the best drug candidates early in the drug development cycle. Drug absorption from the gastrointestinal (GI) tract is affected by many factors. Besides the physiological conditions of the GI tract (e.g., absorptive surface area, local pH, food effects, intestinal transit time, and passive intestinal permeability) and chemical properties of the drug (e.g., solubility, molecular size, and stability), intestinal transporters and enzymes are being increasingly implicated in controlling oral drug absorptio
