A compartmental absorption and transit model for estimating oral drug absorption

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Abstract

This report describes a compartmental absorption and transit model to estimate the fraction of dose absorbed and the rate of drug absorption for passively transported drugs in immediate release products. The model considers simultaneous small intestinal transit flow and drug absorption. Both analytical and numerical methods were utilized to solve the model equations. It was found that the fraction of dose absorbed can be estimated by Fa=1−(1+0.54 Peff)−7, where Peff is the human effective permeability in cm/h. A good correlation was found between the fraction of dose absorbed and the effective permeability for ten drugs covering a wide range of absorption characteristics. The model was able to explain the oral plasma concentration profiles of atenolol.

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)

  • D.S. Davies

    Pharmacokinetics of terbutaline after oral administration

    Eur. J. Resp. Dis. Suppl.

    (1984)
  • E. Eichelbaum et al.

    Pharmacokinetics and metabolism of antipyrine after intravenous and oral administration

    Arzneim-Forsch.

    (1982)
  • U. Fagerholm et al.

    The influence of net water absorption on the small intestinal permeability of terbutaline, studied in vivo in man

    J. Drug Target.

    (1995)
  • Cited by (0)

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