- Please check and comment entries here.
Oral Bioavailability and Regulatory Aspects
Oral bioavailability refers to the extent a substance or drug becomes completely available to systemic circulation or to its intended biological destination(s) via the oral route. High oral bioavailability reduces the amount of a drug necessary to achieve a desired pharmacological effect, therefore reducing the risk of side-effects and toxicity. Low oral bioavailability results in low efficacy and is a major reason for drug candidates failing to reach the market. Hence, oral bioavailability is one of the most important properties in drug design and development.
The intestinal epithelium critically contributes to oral bioavailability of drugs by constituting an important site for drug absorption and metabolism. In particular, intestinal epithelial cells (IEC) actively serve as gatekeepers of drug and nutrient availability. IEC transport processes and metabolism are interrelated to the whole-body metabolic state and represent potential points of origin as well as therapeutic targets for a variety of diseases. Human intestinal organoids represent a superior model of the intestinal epithelium, overcoming limitations of currently used in vitro models. Caco-2 cells or rodent explant models face drawbacks such as their cancer and non-human origin, respectively, but are commonly used to study intestinal nutrient absorption, enterocyte metabolism and oral drug bioavailability, despite poorly correlative data. In contrast, intestinal organoids allow investigating distinct aspects of bioavailability including spatial resolution of transport, inter-individual differences and high-throughput screenings. As several countries have already developed strategic roadmaps to phase out animal experiments for regulatory purposes, intestinal organoid culture and organ-on-a-chip technology in combination with in silico approaches are roads to go in the preclinical and regulatory setup and will aid implementing the 3Rs (reduction, refinement and replacement) principle in basic science.
2. Oral Bioavailability
3. Future Directions
The entry is from 10.3390/pharmaceutics13081280
- Currie, G.M. Pharmacology, part 2: Introduction to pharmacokinetics. J. Nucl. Med. Technol. 2018, 46, 221–230.
- Dietrich, C.G.; Geier, A.; Oude Elferink, R.P. Abc of oral bioavailability: Transporters as gatekeepers in the gut. Gut 2003, 52, 1788–1795.
- Wenzel, U.; Kuntz, S.; Diestel, S.; Daniel, H. Pept1-mediated cefixime uptake into human intestinal epithelial cells is increased by Ca2+ channel blockers. Antimicrob. Agents Chemother. 2002, 46, 1375–1380.
- Brocks, D.R.; Davies, N.M. Lymphatic drug absorption via the enterocytes: Pharmacokinetic simulation, modeling, and considerations for optimal drug development. J. Pharm. Pharm. Sci. 2018, 21, 254s–270s.
- Langhans, W.; Leitner, C.; Arnold, M. Dietary fat sensing via fatty acid oxidation in enterocytes: Possible role in the control of eating. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011, 300, R554–R565.
- Ramachandran, D.; Clara, R.; Fedele, S.; Michel, L.; Burkard, J.; Kaufman, S.; Diaz, A.A.; Weissfeld, N.; De Bock, K.; Prip-Buus, C.; et al. Enhancing enterocyte fatty acid oxidation in mice affects glycemic control depending on dietary fat. Sci. Rep. 2018, 8, 10818.
- Ebert, K.; Witt, H. Fructose malabsorption. Mol. Cell Pediatr. 2016, 3, 10.
- VanDussen, K.L.; Marinshaw, J.M.; Shaikh, N.; Miyoshi, H.; Moon, C.; Tarr, P.I.; Ciorba, M.A.; Stappenbeck, T.S. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 2015, 64, 911–920.
- Zietek, T.; Giesbertz, P.; Ewers, M.; Reichart, F.; Weinmüller, M.; Urbauer, E.; Haller, D.; Demir, I.E.; Ceyhan, G.O.; Kessler, H.; et al. Organoids to study intestinal nutrient transport, drug uptake and metabolism—Update to the human model and expansion of applications. Front. Bioeng. Biotechnol. 2020, 8, 1065.
- Zietek, T.; Rath, E.; Haller, D.; Daniel, H. Intestinal organoids for assessing nutrient transport, sensing and incretin secretion. Sci. Rep. 2015, 5, 16831.
- Raasch, M.; Fritsche, E.; Kurtz, A.; Bauer, M.; Mosig, A.S. Microphysiological systems meet hipsc technology—New tools for disease modeling of liver infections in basic research and drug development. Adv. Drug Deliv. Rev. 2019, 140, 51–67.
- Hartung, T. Predicting toxicity of chemicals: Software beats animal testing. EFSA J. 2019, 17, e170710.
- Noorden, R.V. Software beats animal tests at predicting toxicity of chemicals. Nature 2018, 559, 163.
- Comenges, J.M.Z.; Joossens, E.; Benito, J.V.S.; Worth, A.; Paini, A. Theoretical and mathematical foundation of the virtual cell based assay—A review. Toxicol. In Vitro 2017, 45, 209–221.
- Herrmann, K.; Pistollato, F.; Stephens, M.L. Beyond the 3rs: Expanding the use of human-relevant replacement methods in biomedical research. ALTEX Altern. Anim. Exp. 2019, 36, 343–352.
- Pound, P.; Ram, R. Are researchers moving away from animal models as a result of poor clinical translation in the field of stroke? An analysis of opinion papers. BMJ Open Sci. 2020, 4, e100041.
- Smirnova, L.; Kleinstreuer, N.; Corvi, R.; Levchenko, A.; Fitzpatrick, S.C.; Hartung, T. 3s—Systematic, systemic, and systems biology and toxicology. ALTEX Altern. Anim. Exp. 2018, 35, 139–162.
- Urani, C.; Bruschi, M.; Casati, S.; Gribaldo, L. Use of alternative methods: From fundamental to industrial research. ALTEX Altern. Anim. Exp. 2019, 36, 320–321.
- Veening-Griffioen, D.H.; Ferreira, G.S.; van Meer, P.J.K.; Boon, W.P.C.; Gispen-de Wied, C.C.; Moors, E.H.M.; Schellekens, H. Are some animal models more equal than others? A case study on the translational value of animal models of efficacy for alzheimer’s disease. Eur. J. Pharmacol. 2019, 859, 172524.
- Mullard, A. Parsing clinical success rates. Nat. Rev. Drug Discov. 2016, 15, 447–448.
- Wong, C.H.; Siah, K.W.; Lo, A.W. Estimation of clinical trial success rates and related parameters. Biostatistics 2019, 20, 273–286.
- Thomas, D.; Burns, J.; Audette, J.; Carroll, A.; Dow-Hygelund, C.; Hay, M. Clinical Development Success Rates 2006–2015; Biotechnology Innovation Organization (BIO): Washington, DC, USA, 2016; pp. 1–16.