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

  • Sheila Annie PetersEmail author
  • Leif Hultin


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.


Physiologically based pharmacokinetic modelling PBPK simulation Drug induced impairment of gastric emptying rate Delayed gastric emptying Inhibition of gastric emptying Pharmacokinetic profile Applications of PBPK simulations 



Physiologically based pharmacokinetics






Intrinsic clearance


Tissue–plasma partition coefficient


Dissociation constant

log  P

Partition coefficient of a substance between lipid and water

log  D6.8

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


Gastric emptying




Area under the curve




Small intestinal


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  1. 1.
    Kido T, Nakai Y, Kase Y, Sakakibara I, Nomura M, Takeda S and Aburada M (2005). Effects of rikkunshi-to, a traditional Japanese medicine, on the delay of gastric emptying induced by N(G)-nitro-L-arginine. J Pharmacol Sci 98: 161–167 PubMedCrossRefGoogle Scholar
  2. 2.
    Wallden J, Thorn SE and Wattwil M (2004). The delay of gastric emptying induced by remifentanil is not influenced by posture. Anesth Analg 99: 429–434 PubMedCrossRefGoogle Scholar
  3. 3.
    Calatayud S, Garcia-Zaragoza E, Hernandez C, Quintana E, Felipo V, Esplugues JV and Barrachina MD (2002). Down regulation of nNOS and synthesis of PGs associated with endotoxin-induced delay in gastric emptying. Am J Physiol Gastrointest Liver Physiol 283: G1360–G1367 PubMedGoogle Scholar
  4. 4.
    Cho SH, Park H, Kim JH, Ryu YH, Lee SI and Conklin JL (2006). Effect of sildenafil on gastric emptying in healthy adults. J Gastroenterol Hepatol 21: 222–226 PubMedCrossRefGoogle Scholar
  5. 5.
    Djaldetti R, Ziv I and Melamed E (1996). Impaired absorption of oral levodopa:a major cause for response fluctuations in Parkinson’s disease. Isr J Med Sci 32: 1224–1227 PubMedGoogle Scholar
  6. 6.
    Harasawa S, Kikuchi K, Senoue I, Nomiyama T and Miwa T (1982). Gastric emptying in patients with gastric ulcers–effects of oral and intramuscular administration of anticholinergic drug. Tokai J Exp Clin Med 7: 551–559 PubMedGoogle Scholar
  7. 7.
    Bozkurt A, Deniz M and Yegen BC (2000). Cefaclor, a cephalosporin antibiotic, delays gastric emptying rate by a CCK-A receptor-mediated mechanism in the rat. Br J Pharmacol 131: 399–404 PubMedCrossRefGoogle Scholar
  8. 8.
    Murphy DB, Sutton JA, Prescott LF and Murphy MB (1997). Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology 87: 765–770 PubMedCrossRefGoogle Scholar
  9. 9.
    Christian L and Andreas R (2005). Development and application of physiologically based pharmacokinetic modelling tools to support drug discovery. Chemistry and biodiversity 2: 1462–1486 CrossRefGoogle Scholar
  10. 10.
    Nestorov I (2003). Whole body pharmacokinetic models. Clin Pharmacokinet 42: 883–908 PubMedCrossRefGoogle Scholar
  11. 11.
    Charnick SB, Kawai R, Nedelman JR, Lemaire M, Niederberger W and Sato H (1995). Perspectives in pharmacokinetics. Physiologically based pharmacokinetic modeling as a tool for drug development. J Pharmacokinet Biopharm 23: 231–235 CrossRefGoogle Scholar
  12. 12.
    Bernareggi A and Rowland M (1991). Physiologic modeling of cyclosporin kinetics in rat and man. J Pharmacokinet Biopharm 19: 21–50 PubMedCrossRefGoogle Scholar
  13. 13.
    Rodgers T, Leahy D and Rowland M (2005). Physiologically based pharmacokinetic modeling 1: Predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci 94: 1259–1276 PubMedCrossRefGoogle Scholar
  14. 14.
    Rodgers T and Rowland M (2006). Physiologically based pharmacokinetic modeling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci 95: 1238–1257 PubMedCrossRefGoogle Scholar
  15. 15.
    Agoram B, Woltosz WS and Bolger MG (2001). Predicting the impact of physiological and biochemical processes on oral drug availability. Adv Drug Deliv Rev 50: S41–S67 PubMedCrossRefGoogle Scholar
  16. 16.
    Winiwarter S, Bonham NM, Ax F, Hallberg A, Lennernas H and Karlen A (1998). Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach. J Med Chem 41: 4939–4949 PubMedCrossRefGoogle Scholar
  17. 17.
    Kawai R, Lemaire M, Steimer J-L, Bruelisauer A, Niederberger W and Rowland M (1994). Physiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125. J Pharmacokinet Biopharm 22: 327–365 PubMedCrossRefGoogle Scholar
  18. 18.
    Davies B and Morris T (1993). Physiological parameters in laboratory animals and humans. Pharm Res 10: 1093–1095 PubMedCrossRefGoogle Scholar
  19. 19.
    Brown RP, Delp MD, Lindstedt ST, Rhomberg LR and Beliles RP (1997). Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13: 407–484 PubMedGoogle Scholar
  20. 20.
    Haruta S, Kawai K, Jinnouchi S, Ogawara K-I, Higaki K, Tamura S, Arimori K and Kimura T (2001). Evaluation of absorption kinetics of orally administered theophylline in rats based on gastrointestinal transit monitoring by gamma scintigraphy. J Pharm Sci 90: 464–473 PubMedCrossRefGoogle Scholar
  21. 21.
    Oberle RL, Chen TS, Lloyd C, Barnett JL, Owyang C, Meyer J and Amidon GL (1990). The influence of the interdigestive migrating myoelectric complex on the gastric emptying of liquids. Gastroenterology 99: 1275–1282 PubMedGoogle Scholar
  22. 22.
    Yu LX and Amidon GL (1998). Characterization of small inetstinal transit time distribution in humans. Int J Pharm 171: 157–163 CrossRefGoogle Scholar
  23. 23.
    Nielson MA, Bayati A and Mattsson H (2006). Wistar Kyoto rats have impaired gastric accommodation compared to Sprague Dawley rats due to increased vagal cholinergic tone. Scand J Gastroenterology 41: 773–781 CrossRefGoogle Scholar
  24. 24.
    Washington N, Washington C and Wilson CG (2001). Physiological Pharmaceutics—barrier to drug absorption. Taylor and Francis, New York Google Scholar
  25. 25.
    Willmann S, Schmitt W, Keldenich J and Dressman JB (2003). A physiologic model for simulating gastrointestinal flow and drug absorption in rats. Pharm Res 20: 1766–1771 PubMedCrossRefGoogle Scholar
  26. 26.
    Oberle RL and Amidon GL (1987). The influence of variable gastric emptying and intestinal transit rate on the plasma level curve of cimetidine: An explanation of the double peak phenomenon. J Pharmacokinet Biopharm 15: 529–544 PubMedCrossRefGoogle Scholar
  27. 27.
    DeSesso JM and Jacobson CF (2001). Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats. Food Chem Toxicol 39: 209–228 PubMedCrossRefGoogle Scholar
  28. 28.
    Eastman IM and Miller EG (1935). Gastrointestinal pH in rats as determined by the glass electrode. J Biol Chem 110: 255–262 Google Scholar
  29. 29.
    Lui CY, Amidon GL, Bereardi RR, Fleisher D, Youngberg C and Dressman JB (1986). Comparison of gastrointestinal pH in dogs and humans: implications on the use of beagle dogs as a model for oral absorption in humans. J Pharm Sci 75: 271–274 PubMedCrossRefGoogle Scholar
  30. 30.
    Crouthamel WG, Abolin CR, Hsieh J and Lim JK (1975). Intestinal pH as a factor in selection of animal models for bioavailability testing. J Pharm Sci 64: 1726–1727 PubMedCrossRefGoogle Scholar
  31. 31.
    Fallingborg J (1999). Intraluminal pH of the human gastrointestinal tract. Dan Med Bull 46: 183–196 PubMedGoogle Scholar
  32. 32.
    Lin HC and Visek WJ (1991). Large intestinal pH and ammonia in rats: dietary fat and protein interactions. J Nutr 121: 832–843 PubMedGoogle Scholar
  33. 33.
    Fagerholm U, Lindhal A and Lennernas H (1997). Regional intestinal permeability in rats of compounds with different physicochemical and transport mechanisms. J Pharm Pharmacol 49: 687–690 PubMedGoogle Scholar
  34. 34.
    Oh DM, Cxurl RL and Amidon GL (1993). Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans: a mathematical model. Pharm Res 10: 264–270 PubMedCrossRefGoogle Scholar
  35. 35.
    Popovic V and Popovic P (1960). Permanent cannulation of aorta and vena cava in rats and ground squirrels. J appl Physiol 15: 727–728 PubMedGoogle Scholar
  36. 36.
    Brage R, Cortijo J, Esplugues J, Esplugues JV, Marti-Bonmati E and Rodriguez C (1986). Effects of calcium channel blockers on gastric emptying and acid secretion of the rat in vivo. Br J Pharmacol 89: 627–633 PubMedGoogle Scholar
  37. 37.
    Yavorski RT, Hallgren SE and Blue PW (1991). Effects of verapamil and diltiazem on gastric emptying in normal subjects. Dig Dis Sci 36: 1274–1276 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Global Compound Sciences, Computational ChemistryAstrazeneca R&DMolndalSweden
  2. 2.Integrative PharmacologyAstrazeneca R&DMolndalSweden

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