Pharmacokinetics of Drug Absorption and Metabolism: Mechanisms, Influencing Factors, and Screening Strategies in Drug Development
Keywords:
Drug Absorption, Drug Metabolism, CYP450 Enzymes, Pharmacokinetics, BioavailabilityAbstract
The pharmacokinetics of drug absorption and metabolism play a crucial role in determining therapeutic efficacy and safety. Drug absorption, primarily occurring in the small intestine, is influenced by various physicochemical and physiological factors, including solubility, particle size, gastrointestinal motility, and metabolic enzyme activity. The intestinal epithelium serves as both an absorption site and a barrier, impacting oral drug bioavailability through first-pass metabolism involving Phase I and Phase II reactions. Following absorption, drugs undergo distribution, metabolism, and excretion, with the liver being the primary site of biotransformation, largely mediated by the cytochrome P450 (CYP450) enzyme system. Understanding drug metabolism is critical for pharmaceutical development, particularly in predicting drug interactions and toxicity. This review explores key mechanisms, influencing factors, and screening strategies used in drug absorption and metabolism studies, emphasizing their significance in drug discovery and regulatory sciences.
Downloads
Metrics
References
Currie GM. Pharmacology, part 2: introduction to pharmacokinetics. Journal of nuclear medicine technology. 2018 Sep 1;46(3):221-30.
Li Y, Meng Q, Yang M, Liu D, Hou X, Tang L, Wang X, Lyu Y, Chen X, Liu K, Yu AM. Current trends in drug metabolism and pharmacokinetics. Acta Pharmaceutica Sinica B. 2019 Nov 1;9(6):1113-44.
Charles B. Population pharmacokinetics: an overview. Australian Prescriber. 2014 Dec 1;37(6).
Heykants J, Van Peer A, Van de Velde V, Van Rooy P, Meuldermans W, Lavrijsen K, Woestenborghs R, Van Cutsem J, Cauwenbergh G. The clinical pharmacokinetics of itraconazole: an overview. mycoses. 1989 Nov;32:67-87.
Wilson TH, Wiseman G. The use of sacs of everted small intestine for the study of the transferen of substances from the mucosal to the serosal surface. J Physiol 1954;123:116-25.
Leppert PS, Fix JA. Use of everted intestinal rings for in vitro examination of oral absorptica potential. J Pharm Sci 1994;83:976-81.
Hillgren KM, Kato A, Borchardt RT. In vitro systems for studying intestinal drug absorption. Med Res Rev 1995;15: 83-109.
Chowhan ZT, Amaro AA. Everted rat intestinal sacs as an in vitro model for assessing absorptivity new drugs. J Pharm Sci 1977;66:1249-53.
Carrreno Gomez B, Duncan R. Everted rat intestinal sacs: a new model for the quantification of P-glycoprotein mediated efflux of anticancer agents. Anticancer Res 2000:20:3157-61.
Barthe L, et al 1998. An improved everted gut sac as a simple and accurate technique to measure paracellular transport across the small intestine. Eur J Drug Metab Pharmacokinet 1998:23(2):313-23.
Alam MA, Al-Jenoobi FI, Abdullah MA. Everted gut sac model as a tool in pharmaceutical research: limitations and applications. J Pharm Pharmacol 2011;64:326-36.
Ussing HH, Zerahn K. Active transport of sodium as the source of electric current in the short- circuited isolated frog skin. Acta Physiol Scand 1951:23:110-27.
Jezyk N, Li C. Stewart BH, et al. Transport of pregabalin in rat intestine and Caco-2 monolayers. Pharm Res 1999;16:519-26.
Ungell AL, Andreason A, Lundin K, Utter L. Effects of enzymatic inhibition and increased paracellular shunting on transport of vasopressin analogues in the rat J. Pharma Sci 1992:81:640-5.
Soderholm JD, Hedman L. Artursson P, et al. Integrity and metabolism of human ileal mucosa in vitro in the Ussing chamber. Acta Physiol Scand 1998;162:47-56. Polentarutti Bl, Peterson AL, Sjoberg AK, Anderberg EKI., Utter LM, Ungell AL. Evaluation of viability of excised rat intestinal segments in the Ussing chamber:investigation of morphology, electrical parameters and permeability characteristics. Pharma Res 1999;16(3):446-54.
Westerhout J, van de Steeq E, Grossouw D, et al. A new approach to predict human intestinal absorption using porcine intestinal tissue and biorelevant matrices. Eur J Pharm Sci 2014,63:167-77.
Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998;101:289-94.
Pauli-Magnus C, von Richter O, Burk O, et al. Characterization of the major metabolites of verapamil as substrates and inhibitors of P-glycoprotein. J Pharmacol Exp Ther 2000;293:376- 82.
Artursson P. Karlsson J. Correlation between oral absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun 1991;175:880-5.
van Breemen RB, Li Y. Caco-2 cell permeability assays to measure drug absorption. Expert Opin Drug Metab Toxicol 2005;1(2):175-85.
Collet A. Sims E, Walker D, et al. Comparison of HT 29-18-C1 and Caco-2 cell lines as models for intestinal paracellular drug absorption. Pharm Res 1996;13(2):216-21.
Gaush CR, Hard WL, Smith TF. Characterization of an established line of canine kidney cells (MDCK). Proc Soc Exp Biol Med 1966:122:931-5.
Quaroni A, Beaulieu JF. Cell dynamics and differentiation of conditionally immortalized human intestinal epithelial cells. Gastroenterology 1997;113:1198-213.
Blay J, Brown KD. Characterization of an epithelioid cell line derived from rat small intestine: demonstration of cytokeratin filaments. Cell Biol Int Rep 1984:8:551-60.
Komiya 1, Park JY, Kamani A, et al. Quantitative mechanistic studies in simultaneously fluid flow and intestinal absorption using steroids as model solutes. Int J Pharm 1979;4:249-62.
Doluisio JT, Billups NF, Dittert LW, et al. Drug absorption. I. An in situ rat gut technique yielding realistic absorption rates. J Pharm Sci 1969:58:1196-200.
Sjogren E, Westergren 1, Grant L, et al. In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. Eur J Pharm Sci 2013;49(4):679-98.
Brandon Esther FA, Raap Christiaan D, Meijerman I, et al. An update on in vitro test methods in human hepatic drug biotransformation research:pros and cons. Toxicol Applied Pharmacol 2003;189:233-46.
Emoto C, Murayama N, Rostami-Hodjegan A, et al. Methodologies for investigating drug metabolism at the early drug discovery stage: prediction of hepatic drug clearance and P450 contribution. Current Drug Metab 2010;11(8):678-85.
Zhang D, Luo G, Ding X, et al. Preclinical experimental models of drug metabolism and disposition in drug discovery and development. Acta Pharmaceutica Sinica B 2012;2(6):549-61.
Lamba JK, Lin YS, Schuetz EG, et al. Genetic contribution to variable human CYP3A- mediated metabolism. Adv Drug Deliv Rev 2002;54(10):1271-4.
Bissell DM, Hammaker LE, Meyer UA. Parenchymal cells from adult rat liver in nonproliferating monolayer culture I Functional Studies. J Cell Biol 1973:59:722-34.
Palma E, Doornebal EJ, Chokshi S. Precision-cut liver slices: a versatile tool to advance liver research. Hepatology international. 2019 Jan 15;13:51-7.
Dewyse L, Reynaert H, van Grunsven LA. Best practices and progress in precision-cut liver slice cultures. International journal of molecular sciences. 2021 Jul 1;22(13):7137.
Olinga P, Schuppan D. Precision-cut liver slices: a tool to model the liver ex vivo. Journal of hepatology. 2013 Jun;58(6):1252-3.
Gandolfi AJ, Wijeweera J, Brendel K. Use of precision-cut liver slices as an in vitro tool for evaluating liver function. Toxicologic pathology. 1996 Jan;24(1):58-61.
Van de Bovenkamp M, Groothuis GM, Meijer DK, Olinga P. Liver fibrosis in vitro: cell culture models and precision-cut liver slices. Toxicology in vitro. 2007 Jun 1;21(4):545-57.
Hutchings SE, Sato GH. Growth and maintenance of HeLa cells in serum-free medium supplemented with hormones. Proc Natl Acad Sci USA 1978;75:901-4.
Sahi J, Grepper S, Smith C. Hepatocytes as a tool in drug metabolism, transport and safety evaluations in drug discovery. Curr Drug Discov Technol 2010;7(3):188-98.
Li AP. In vitro human hepatocyte-based experimental systems for the evaluation of human drug metabolism, drug-drug interactions, and drug toxicity in drug development. Curr Top Med Chem 2014;14(11):1325-38.
Steensma A, Beamand JA, Walters DG, et al. Metabolism of coumarin and 7- ethoxycoumarin by rat, mouse, guinea pig, cynomolgus monkey and human precision-cut liver slices. Xenobiotica 1994:24:893-907.
Zuber R, Anzenbacherova, Anzenbacher P. Cytochromes P450 and experimental models of drug metabolism. J Cell Mol Med 2002;6(2):189-98.
Bend JR, Hook GE, Easterling RE, et al. A comparative study of the hepatic and pulmonary
microsomal mixed-function oxidase systems in the rabbit. J Pharmacol Exp Ther 1972;183:206-
17. 36. Lowry OH, Rosebrough NJ, Farr AL., et al. Protein measurement and folin phenol reagent. J Biol Chem 1951;93:265-75.
Kroemer HK, Echizen H, Heidemann H, et al. Predictability of the in vivo metabolism of verapamil from in vitro data: contribution of individual metabolic pathways and stereoselective aspects. I Pharmacol Exp Ther 1992:260:1052-7.
Birkett DJ, Mackenize PI, Veronese ME, et al. In vitro approaches can predict human drug metabolism. Trends Pharmacol Sci 1993;4:292.
Doehmer J. Oesch F. V79 Chinese hamster cells genetically engineered for stable expression of cytochrome P450. Methods Enzymol 1991;206:117-23.
Gautier JC, Urban P, Beaune P, et al. Engineered yeast cells as model to study coupling between human xenobiotic metabolizing enzymes. Simulation of the two first steps on benzo[a]pyrene activation. Eur J Biochem 1993;211:63-72.
Lee CA, Kadwell SH, Kost TA, et al. CYP3A4 expressed by insect cells infected with a recombinant baculovirus containing both CYP3A4 and human NADPH-cytochrome P450 reductase is catalytically similar to human liver microsomal CYP3A4. Arch Biochem Biophys 1995;319:157-67.
Guengerich FP, Martin MV, Guo Z, et al. Purification of functional recombinant P450s from bacteria. Methods Enzymol 1996;272:35-44.
Friedberg T, Tritchard MP, Bandera M, et al. Merits and limitations of recombinant models for the study of human P 450 mediated drug metabolism and toxicity:an inter laboratory comparison. Drug Metab Rev 1999;31(2):523-44
Downloads
Published
How to Cite
Issue
Section
License

This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
Terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.