Abstract
Purpose. The development of a physiologically based absorption model for orally administered drugs in rats is described.
Methods. Unlike other models that use a multicompartmental approach, the GI tract is modeled as a continuous tube with spatially varying properties. The mass transport through the intestinal lumen is described via an intestinal transit function. The only substance-specific input parameters of the model are the intestinal permeability coefficient and the solubility in the intestinal fluid. With this physiologic and physicochemical information, the complete temporal and spatial absorption profile can be calculated.
Results. A first performance test using portal concentration data published in the literature yielded an excellent agreement between measured and simulated temporal absorption profiles in the portal vein. Furthermore, the dose dependence of a compound with solubility-limited fraction dose absorbed in rats (chlorothiazide) could be adequately described by the model.
Conclusions. The continuous absorption model is well suited to simulate drug flow and absorption in the GI tract of rats.
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References
R. A. Prentis, Y. Lis, and S. R. Walker. Pharmaceutical innovation by the seven U.K.owned pharmaceutical companies (1964–1985). Br. J. Clin. Pharmacol. 25:387-396 (1988).
S. Venkatesh and R. A. Lipper. Role of the development scientist in compound lead selection and optimization. J. Pharm. Sci. 89:145-154 (2000).
M. Bajpai and K. K. Adkinson. High throughput screening for lead optimization: a rational approach. Curr. Opin. Drug Discov. Dev. 3:63-71 (2000).
P. Poulin and F.P. Theil. A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. J. Pharm. Sci. 89:16-35 (2000).
D. A. Norris, G. D. Leesman, P. J. Sinko, and G. M. Grass. Development of predictive pharmacokinetic simulation models for drug discovery. J. Control. Rel. 65:55-62 (2000).
T. Lave, O. Luttringer, J. Zuegge, G. Schneider, P. Coassolo, and F.P. Theil. Prediction of human pharmacokinetics based on preclinical in vitro and in vivo data. Ernst Schering Res. Found. Workshop 37:81-104 (2002).
G. M. Grass and P. J. Sinko. Physiologically-based pharmacokinetic simulation modelling. Adv. Drug Deliv. Rev. 54:433-451 (2002).
G. M. Grass. Simulation models to predict oral drug absorption from in vitro data. Adv. Drug Deliv. Rev. 23:199-219 (1997).
L. X. Yu. An integrated model for determining causes of poor oral drug absorption. Pharm. Res. 16:1883-1887 (1999).
Y. Plusquellec, C. Efthymiopoulos, P. Duthil, and G. Houin. A pharmacokinetic model for multiple sites discontinuous gastrointestinal absorption. Med. Eng. Phys. 21:525-532 (1999).
L. X. Yu and G. L. Amidon. A compartmental absorption and transit model for estimating oral drug absorption. Int. J. Pharm. 186:119-125 (1999).
B. Agoram, W. S. Woltosz, and M. B. Bolger. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv. Drug Del. Rev. 50:41-67 (2001).
http://www.lionbioscience.com/solutions/products/idea-
http://www.simulations-plus.com/products/gastro_plus.html-
R. Hebel and M. W. Stromberg. Anatomy of the Laboratory Rat, Lippincott Williams & Wilkins, Baltimore, 1976.
R. B. Fischer and D. S. Parsons. The gradient of mucosal surface area in the small intestine of the rat. J. Anat. 84:272-282 (1957).
L. Poulakos and T. H. Kent. Gastric emptying and small intestinal propulsion in fed and fasted rats. Gastroenterology 64:962-967 (1973).
T. T. Kararli. Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm. Drug Dispos. 16:351-380 (1995).
T. Sawamoto, S. Haruta, Y. Kurosaki, K. Higaki, and T. Kimura. Prediction of the plasma concentration profiles of orally administered drugs in rats on the basis of gastrointestinal transit kinetics and absorbability. J. Pharm. Pharmacol. 49:450-457 (1997).
W. H. Press, S. A. Teukolsky, W. T. Vetterling, and B. P. Flannery. Numerical Recipes in C—The Art of Scientific Computing, 2nd ed. Cambridge University Press, Cambridge, 1992.
T. Moriwaki, H. Yasui, Y. Shigemoto, and N. H. Yoshida. A recirculatory model for local absorption and disposition of ciprofloxacin by measuring portal and systemic blood concentration difference. J. Pharm. Sci. 91:196-205 (2002).
Y. Fujieda, K. Yamaoka, T. Ito, and T. Nakagawa. Local absorption kinetics of levofloxacin from intestinal tract into portal vein in conscious rat using portal-venous concentration difference. Pharm. Res. 13:1201-1204 (1996).
K. Tabata, K. Yamaoka, T. Fukuyama, and T. Nakagawa. Local absorption kinetics into the portal system using the portal-venous concentration difference after an oral dose of diclofenac in the awakening rat. Drug. Metab. Disp. 24:216-220 (1996).
S. Ueda, K. Yamaoka, and T. Nakagawa. Effect of pentobarbital anesthesia on intestinal absorption and hepatic first-pass metabolism of oxacillin evaluated by the portal-systemic concentration difference, www.pharm.kyoto-u.ac.jp/ueda-
F.H. Hsu, T. Prueksaritanont, M. G. Lee, and W. L. Chiou. The Phenomenon and Cause of the Dose-Dependent Oral Absorption of Chlorothiazide in Rats: Extrapolation to Human Data Based on the Body Surface Area Concept. J. Pharmacokin. Biopharm. 15:369-386 (1987).
Syracuse Research Corporation. PHYSPROP—The Physical Properties Database, http://esc.syrres.com/interkow/PhysProp.htm-
A. Frick, H. Möller, and E. Wirbitzki. Biopharmaceutical characterization of oral immediate release drug products. In vitro/in vivo comparison of phenoxymethylpenicillin potassium, glimepiride and levofloxacin. Eur. J. Pharm. Biopharm. 46:305-311 (1998).
J. B. Dressman, D. Fleisher, and G. L. Amidon. Physicochemical model for dose-dependent drug absorption. J. Pharm. Sci. 73:1274-1279 (1984).
W. L. Chiou, C. Ma, S. M. Chung, T. C. Wu, and H. Y. Jeong. Similarity in the linear and non-linear oral absorption of drugs between human and rat. Int. J. Clin. Pharmacol. Ther. 38:532-539 (2000).
V. D. Makhey, A. Guo, D. A. Norris, P. Hu, J. Yan, and P. J. Sinko. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells. Pharm. Res. 15:1160-1167 (1989).
P. S. Burton, J. T. Goodwin, T. J. Vidmar, and B. M. Amore. Predicting drug absorption: how nature made it a difficult problem. J. Pharmacol. Exp. Ther. 303:89-95 (2002).
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Willmann, S., Schmitt, W., Keldenich, J. et al. A Physiologic Model for Simulating Gastrointestinal Flow and Drug Absorption in Rats. Pharm Res 20, 1766–1771 (2003). https://doi.org/10.1023/B:PHAM.0000003373.72652.c0
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DOI: https://doi.org/10.1023/B:PHAM.0000003373.72652.c0