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Early identification of drug-induced impairment of gastric emptying through physiologically based pharmacokinetic (PBPK) simulation of plasma concentration-time profiles in rat

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Abstract

Inhibition of gastric emptying rate can have adverse effects on the absorption of food and nutrients. The absorption phase of the plasma concentration-time profile of a compound administered orally to pre-clinical species reflects among others, the gastric and intestinal transit kinetics, and can thus assist in the early identification of delayed gastric emptying. The purpose of this article is to demonstrate the value of Physiologically Based Pharmacokinetic (PBPK) modelling in the early identification of drug induced impairment of gastric emptying from pharmacokinetic profiles. To our knowledge, this is first time that the value of a generic PBPK model for hypothesis testing has been demonstrated with examples. A PBPK model built in-house using MATLAB package and incorporating absorption, metabolism, distribution, biliary and renal elimination models has been employed for the simulation of concentration-time profiles. PBPK simulations of a few compounds that are currently in drug discovery projects show that the observed initial absorption phase of their concentration-time profiles in rat were consistent with reduced gastric emptying rates. The slow uptake of these compounds into the systemic circulation is reflected in their pharmacokinetic profiles but it is not obvious until PBPK simulations are done. Delayed gastric emptying rates of these compounds in rats were also independently observed in x-ray imaging. PBPK simulations can provide early alerts to drug discovery projects, besides aiding the understanding of complex mechanisms that determine the lineshapes of pharmacokinetic profiles. The application of PBPK simulations in the early detection of gastric emptying problems with existing data and without the need to resort to additional animal studies, is appealing both from an economic and ethical standpoint.

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Abbreviations

PBPK:

Physiologically based pharmacokinetics

PK:

Pharmacokinetics

iv:

Intravenous

CL int :

Intrinsic clearance

Kp :

Tissue–plasma partition coefficient

pK a :

Dissociation constant

log  P :

Partition coefficient of a substance between lipid and water

log  D 6.8 :

Distribution coefficient of a substance between lipid and water at pH 6.8

GE:

Gastric emptying

P-gp:

P-glycoprotein

AUC:

Area under the curve

GI:

Gastrointestinal

SI:

Small intestinal

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Authors and Affiliations

  1. Global Compound Sciences, Computational Chemistry, Astrazeneca R&D, Pepparedsleden 1, 43183, Molndal, Sweden

    Sheila Annie Peters

  2. Integrative Pharmacology, Astrazeneca R&D, Pepparedsleden 1, 43183, Molndal, Sweden

    Leif Hultin

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  1. Sheila Annie Peters
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Correspondence to Sheila Annie Peters.

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Peters, S.A., Hultin, L. Early identification of drug-induced impairment of gastric emptying through physiologically based pharmacokinetic (PBPK) simulation of plasma concentration-time profiles in rat. J Pharmacokinet Pharmacodyn 35, 1–30 (2008). https://doi.org/10.1007/s10928-007-9073-1

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  • DOI: https://doi.org/10.1007/s10928-007-9073-1

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