A compartmental absorption and transit model for estimating oral drug absorption
Introduction
Estimating intestinal drug absorption kinetics can greatly facilitate lead drug candidate selection and support formulation strategies. Quantitative and mechanistic approaches have been developed since the traditional approach to treat the entire gastrointestinal tract as a single-compartment ‘black box’ does not suffice (Ho et al., 1983, Dressman et al., 1984, Sinko et al., 1991). The utilities and limitations of these quantitative and mechanistic models have been discussed in a recent review article (Yu et al., 1996a). Although gastric emptying and small intestinal transit flow can influence the rate and extent of drug absorption after oral administration, none of the previous models have fully considered these factors. The aim of this report was to develop a compartmental absorption and transit (CAT) model for estimating the fraction of dose absorbed and the rate of drug absorption based on the transit models (Yu et al., 1996b, Yu and Amidon, 1998). We derived an equation to correlate the fraction of dose absorbed with the human effective permeability. The CAT model was related to compartmental pharmacokinetic models to evaluate the effect of gastric emptying on plasma concentration profiles.
Section snippets
Theoretical
Fig. 1 illustrates the CAT model to account for the transit flow in the stomach, duodenum, jejunum, and ileum, and the passive absorption in the duodenum, jejunum, and ileum. The gastrointestinal tract is divided into three segments: stomach, small intestine, and colon. The transit flow in the human small intestine can be described by seven compartments, where a drug transfers from one compartment to the next one in a first-order fashion (Yu et al., 1996b). The colon is considered only as a
Computer simulation
Model 1–3 and 13–15 are a typical initial value problem of an ordinary differential equation system. This system was numerically solved by the ADAPT pharmacokinetic and pharmacodynamic modeling package (D’Argenio and Schumitzky, 1992). A subroutine was written to accommodate the model equations.
Estimating fraction of dose absorbed
Ten compounds covering a wide range of absorption characteristics, from enalaprilat (the least permeable) to ketoprofen (the most permeable), were chosen to evaluate the predictability of the model. The
Estimating fraction of dose absorbed
Fig. 2 shows the predicted values. The fraction of dose absorbed for enalaprilat in laboratory animals was estimated to be only 5–12%; in humans, oral absorption of radiolabelled enalaprilat was probably less than 10% (Kubo and Cody, 1985). The model predicted the fraction of dose absorbed to be 26% for enalaprilat, higher than the experimental value. The fraction of dose absorbed for furosemide varies from 37 to 83% in healthy volunteers and the mean value is around 55% (Ponto and Schoenwald,
Conclusions
This report describes a compartmental absorption and transit model to estimate oral drug absorption of passively transported drugs. A simple equation was derived which predicts the fraction of dose absorbed reasonably well. The CAT model offers the advantages of being able to estimate the rate of drug absorption and couple easily with compartmental pharmacokinetics models. The simulation study showed that gastric emptying could cause double peaks in oral plasma concentration profiles.
Acknowledgements
The authors would like to thank Avis Bridgers, Ambrish Vyas, and Mark Sacchetti for reviewing the manuscript.
References (26)
- et al.
Physicochemical model for dose-dependent drug absorption
J. Pharm. Sci.
(1984) - et al.
Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of oral drug absorption
Adv. Drug Del. Rev.
(1996) - et al.
Compartmental transit and dispersion model analysis of small intestinal transit flow in humans
Int. J. Pharm.
(1996) - et al.
Characterization of small intestinal transit time distribution in humans
Int. J. Pharm.
(1998) - American Hospital Formulary Service. 1998 Edition, pp....
- et al.
A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability
Pharm. Res.
(1995) - Amidon, G.L., 1996. Unpublished...
- et al.
Design and optimization of dosage regiments; pharmacokinetic data
- et al.
Kinetics of acetaminophen absorption and gastric emptying in man
Clin. Pharmacol. Ther.
(1978) - D’Argenio, D.Z., Schumitzky, A. 1992. Adapt II: Mathematical Software for Pharmacokinetics/Pharmacodynamics Systems...