Abstract

Citation

Researchers should cite this work as follows:

• Wedenberg, M. (2023). 2005-Minna_Wedenberg-Pharmacokinetic modeling of gastric emptying. SIMIODE, QUBES Educational Resources. doi:10.25334/SCSE-W597

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Article Context

Description

Wedenberg, Minna. 2005. Pharmacokinetic modeling of gastric emptying and small intestinal transit time in dogs using paracetamol and sulfasalazine as markers. Master’s Degree Project.  Uppsala Universitet. 41 pp.

See https://www.uu.se/digitalAssets/165/c_165171-l_3-k_wedenberg-minna-arbete.pdf . Accessed 27 March 2023.

From the introduction

The development of new drug substances is a complex, time consuming and expensive process. Reducing the time for drug development and avoiding late termination of candidate drugs are important challenges for the pharmaceutical industry.

Adverse effects due to altered gastrointestinal function have been reported to account for around 18% of all adverse drug reactions (Lewis, 1986). This includes diarrheas, constipation and other reactions directly related to gastrointestinal transit. Altered gastrointestinal transit or gastric emptying rates may also affect the total uptake of other drug substances. As a consequence, it is desirable to be able to screen for drug substances that alter the gastrointestinal transit already in an early stage of the drug development process.

There are different approaches to estimate the gastric emptying rate and gastrointestinal transit time. Scintigraphic measurement uses radioactive isotopes and image analysis (Iwanaga et al., 1998). In breath tests, an isotope (for example 13C) is given orally and the level of particles in the breath marked by that isotope (for example 13CO2) is measured (Lee et al., 2000). These have disadvantages in terms of costs or invasiveness. In the present investigation, we use the double marker technique which is based on measurements of the plasma levels for two drug substances that are absorbed in different parts of the gastrointestinal system (Mizuta et al., 1990). Because it may be difficult to accurately estimate when a drug substance first appears in the plasma based on observations (at least when their number is limited), pharmacokinetic models are used.

The pharmacokinetic models used for predicting and analyzing the pharmacokinetic profiles of drug substances administered orally are simplifications of complex processes. Specifically, although gastric emptying and transit time can affect drug absorption these processes are seldom taken into account (Yu and Amidon, 1999). In this thesis, two pharmacokinetic models are considered: the standard model and the transit rate model. The standard model consists of an absorption compartment and a central compartment where the measurements are made (the plasma). It does not explicitly account for the gastric emptying rate and the intestinal transit time. The transit rate model does. It divides the gastrointestinal tract into the stomach, the small intestine and the colon. The small intestine is, in turn, further partitioned into six segments and the flow through the segments is described by first order kinetics. Simulations are also carried out for a lag time model. This model also divides the gastrointestinal tract into the stomach, the small intestine and the colon, but is based on residence times rather than transit rates.

Keywords: pharmacokinetic, small intestine, stomach, model, differential equation, system, sensitivity analysis, simulation, paracetamol, data, graphs, sulfapyridine, parameter estimate