Taking drug compounds on the ride to absorption
Even highly potent drug candidates have limited practical utility if the drug is not well-absorbed. Professor Christopher Porter says low water solubility and poor target specificity present a significant challenge for drug development. Chris is researching the fundamentals of how drugs are absorbed and distributed to their sites of action, and aims to develop drug delivery systems to enhance their clinical utility.
Chris is Professor of Pharmaceutics at the Monash Institute of Pharmaceutical Sciences and Associate Dean of Research in the Faculty of Pharmacy and Pharmaceutical Sciences. Chris’ group works to address the poor oral absorption of drugs with intrinsically low water solubility, and to develop delivery systems to enhance the activity and reduce the toxicity of anti-cancer agents.
Unfortunately, more than 50 per cent of drug candidates have low water solubility. Compounds such as this are poorly absorbed after oral administration since drugs must pass into solution in the fluids of the gastrointestinal tract before they can be absorbed.
“The problem of poorly-water-soluble drugs is not insignificant because the properties that make drugs bind to receptors most effectively, and therefore that increase potency, simultaneously reduce solubility in water,” Chris explains. “That’s a problem if you want to give drugs orally.
"However, we do know that the body has developed myriad systems to deal with the absorption of dietary fats and lipids, which have similar characteristics to many poorly-water-soluble drugs. Much of my research is about understanding the ways in which the body has evolved to deal with dietary lipids, and applying that understanding to improving the absorption of poorly water-soluble drugs.”
A series of events in the gastrointestinal tract (GI tract) and the absorptive cells that line the GI tract promote the absorption of dietary lipids.
“When we eat fat, a cascade of events is stimulated to help the body absorb those materials. For example, pancreatic enzymes are secreted to promote digestion and bile is secreted from the gall bladder. One of the functions of bile acids is to act like a detergent, solubilising the lipid digestion products and forming a reservoir that allows for very efficient absorption. When we co-administer a drug with lipids we can piggyback drug absorption onto the back of this natural lipid absorption process. We are currently attempting to develop in vitro models of this lipid digestion process to help us identify the ideal lipids with which to promote drug absorption.”
Chris is also collaborating with Melbourne-based biotechnology company, Starpharma, to develop dendrimers into nanomedicines to better deliver drugs to their intended target.
“Dendrimers are branched polymers that can be synthesised with almost infinite complexity but also with great precision and therefore provide an excellent vehicle for the delivery of drugs. With Starpharma we are exploring the utilisation of dendrimers to improve drug delivery in a number of ways, but perhaps the most interesting is the use of dendrimer-based drug delivery systems to improve anti cancer therapy.
"By modifying the structure of these nanomaterials we can promote retention in the blood circulation for long periods of time after a single intravenous injection. Ultimately, this leads to accumulation in tumours, because the blood vessels that supply nutrients to tumours have quite permeable walls. In itself this is promising – but the challenge is to go one step further, and to add specific targeting agents to the surface of these nanomaterials in order to actively direct delivery to particular cell types. This is the area we are focussed on at the moment.”
Lipid-based formulation design,, Nanomedicines, dendrimer-based drug delivery, , Oral drug delivery, bioavailability enhancement, , intracellular binding proteins,, lymphatic drug transport , polyethylen glycol; dendrimer; poly l-lysine; pharmacokinetics, biodistribution
Kaminskas, L., McLeod, V., Kelly, B., Sberna, G., Boyd, B., Williamson, M., Owen, D., Porter, C., 2012, A comparison of changes to doxorubicin pharmacokinetics, antitumour activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems, Nanomedicine-Nanotechnology Biology And Medicine [P], vol 8, issue 1, Elsevier, Netherlands, pp. 103-111.
Kaminskas, L.M., McLeod, V.M., Porter, C.J., Boyd, B.J., 2012, Association of chemotherapeutic drugs with dendrimer nanocarriers: an assessment of the merits of covalent conjugation compared to noncovalent encapsulation, Molecular Pharmaceutics [P], vol 9, issue 3, American Chemical Society, USA, pp. 355-373.
Kaminskas, L.M., McLeod, V.M., Kelly, B.D., Cullinane, C.M., Sberna, G., Williamson, M., Boyd, B.J., Owen, D.J., Porter, C.J., 2012, Doxorubicin-conjugated PEGylated dendrimers show similar tumoricidal activity but lower systemic toxicity when compared to PEGylated liposome and solution formulations in mouse and rat tumour models, Molecular Pharmaceutics [P], vol 9, American Chemical Society, United States, pp. 422-432.
Van Speybroeck, M., Williams, H.D., Nguyen, T., Anby, M.U., Porter, C.J., Augustijns, P., 2012, Incomplete desorption of liquid excipients reduces the in vitro and in vivo performance of self-emulsifying drug delivery systems solidified by adsorption onto an inorganic mesoporous carrier, Molecular Pharmaceutics [P], vol 9, issue 9, American Chemical Society, Washington DC, USA, pp. 2750-2760.
Caliph, S.M., Trevaskis, N., Charman, W.N., Porter, C.J., 2012, Intravenous dosing conditions may affect systemic clearance for highly lipophilic drugs: implications for lymphatic transport and absolute bioavailability studies, Journal of Pharmaceutical Sciences [P], vol 101, issue 9, Wiley-Blackwell, Malden, Massachusetts USA, pp. 3540-3546.
Anby, M.U., Williams, H.D., McIntosh, M.P., Benameur, H., Edwards, G.A., Pouton, C.W., Porter, C.J., 2012, Lipid digestion as a trigger for supersaturation: evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems, Molecular Pharmaceutics [P], vol 9, issue 9, American Chemical Society, USA, pp. 2063-2079.
Williams, H.D., Sassene, P.J., Kleberg, K., Bakala-N'Goma, J., Calderone, M., Jannin, V., Igonin, A., Partheil, A., Marchaud, D., Jule, E., Vertommen, J., Maio, M., Blundell, R., Benameur, H., Carriere, F., Mullertz, A., Porter, C.J., Pouton, C.W., 2012, Toward the establishment of standardized in vitro tests for lipid-based formulations, Part 1: Method parameterization and comparison of in vitro digestion profiles across a range of representative formulations, Journal of Pharmaceutical Sciences [P], vol 101, issue 9, Wiley-Blackwell, Malden, Massachusetts USA, pp. 3360-3380.
Williams, H.D., Anby, M.U., Sassene, P.J., Kleberg, K., Bakala-N'Goma, J., Calderone, M., Jannin, V., Igonin, A., Partheil, A., Marchaud, D., Jule, E., Vertommen, J., Maio, M., Blundell, R., Benameur, H., Carriere, F., Mullertz, A., Pouton, C.W., Porter, C.J., 2012, Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion, Molecular Pharmaceutics [P], vol 9, issue 11, American Chemical Society, Washington DC, USA, pp. 3286-3300.
Trevaskis, N., Charman, W., Porter, C., 2011, Acute hypertriglyceridemia promotes intestinal lymphatic lipid and drug transport: a positive feedback mechanism in lipid and drug absorption, Molecular Pharmaceutics [P], vol 8, American Chemical Society, USA, pp. 1132-1139.
Kaminskas, L., McLeod, V., Sberna, G., Boyd, B., Owen, D., Porter, C., 2011, Capping methotrexate alpha-carboxyl groups enhances systemic exposure and retains the cytotoxicity of drug conjugated PEGylated polylysine dendrimers, Molecular Pharmaceutics [E], vol 8, American Chemical Society, USA, pp. 338-349.
Kaminskas, L., Kelly, B., McLeod, V., Sberna, G., Owen, D., Boyd, B., Porter, C., 2011, Characterisation and tumour targeting of PEGylated polylysine dendrimers bearing doxorubicin via a pH labile linker, Journal of Controlled Release [P], vol 152, Elsevier Science Publishers, The Netherlands, pp. 241-248.
Kaminskas, L., Boyd, B., Porter, C., 2011, Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties, Nanomedicine [P], vol 6, issue 6, Future Medicine, UK, pp. 1063-1084.
Kaminskas, L., McLeod, V., Porter, C., Boyd, B., 2011, Differences in colloidal structure of PEGylated nanomaterials dictate the likelihood of accelerated blood clearance, Journal of Pharmaceutical Sciences [P], vol 11, John Wiley & Sons Inc, USA, pp. 5069-5077.
Trevaskis, N., Nguyen, G., Scanlon, M., Porter, C., 2011, Fatty acid binding proteins: potential chaperones of cytosolic drug transport in the enterocyte?, Pharmaceutical Research [P], vol 28, issue 9, Kluwer Academic/Plenum Publishers, USA, pp. 2176-2190.
Nguyen, T., Hanley, T., Porter, C., Boyd, B., 2011, Nanostructured liquid crystalline particles provide long duration sustained-release effect for a poorly water soluble drug after oral administration, Journal of Controlled Release [P], vol 153, Elsevier, Netherlands, pp. 180-186.
Laguerre, A., Wielens, J., Parker, M., Porter, C., Scanlon, M., 2011, Preparation, crystallization and preliminary X-ray diffraction analysis of two intestinal fatty-acid binding proteins in the presence of 11-(dansylamino)undecanoic acid, Acta Crystallographica Section F: Structural Biology and Crystallization Communications [P], vol 67, issue 2, International Union of Crystallography, United Kingdom, pp. 291-295.
Kaminskas, L., Porter, C., 2011, Targeting the lymphatics using denritic polymers (dendrimers), Advanced Drug Delivery Reviews [P], vol 63, Elsevier Science, Netherlands, pp. 890-900.
Nguyen, T., Hanley, T., Porter, C., Larson, I., Boyd, B., 2010, Phytantriol and glyceryl monooleate cubic liquid crystalline phases as sustained-release oral drug delivery systems for poorly water soluble drugs I. Phase behaviour in physiologically-relevant media, Journal of Pharmacy and Pharmacology [P], vol 62, John Wiley & Sons Ltd., United Kingdom, pp. 844-855.
Nguyen, T., Hanley, T., Porter, C., Larson, I., Boyd, B., 2010, Phytantriol and glyceryl monooleate cubic liquid crystalline phases as sustained-release oral drug delivery systems for poorly water-soluble drugs II. In-vivo evaluation, Journal of Pharmacy and Pharmacology [P], vol 62, issue 7, John Wiley & Sons Ltd., United Kingdom, pp. 856-865.
Trevaskis, N., Charman, W., Porter, C., 2010, Targeted drug delivery to lymphocytes: a route to site-specific immunomodulation?, Molecular Pharmaceutics [P], vol 7, issue 6, American Chemical Society, United States, pp. 2297-2309.
Trevaskis, N., Shanker, R., Charman, W.N., Porter, C.J., 2010, The mechanism of lymphatic access of two cholesteryl ester transfer protein inhibitors (CP524,515 and CP532,623) and evaluation of their impact on lymph lipoprotein profiles, Pharmaceutical Research [P], vol 27, issue 9, Springer, USA, pp. 1949-1964.
Trevaskis, N., McEvoy, C.L., McIntosh, M.P., Edwards, G.A., Shanker, R., Charman, W.N., Porter, C.J., 2010, The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (CP524,515 and CP532,623), Pharmaceutical Research [E], vol 27, Springer Science, USA, pp. 878-893.
Warren, D., Benameur, H., Porter, C.J., Pouton, C.W., 2010, Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: A mechanistic basis for utility, Journal Of Drug Targeting [P], vol 18, issue 10, Informa Healthcare, United Kingdom, pp. 704-731.
Velkov, T., Hughes, M.L.R., Horne, H.J., Simpson, J.S., Porter, C.J., Scanlon, M., 2009, Characterization of lipophilic drug binding to rat intestinal fatty acid binding protein, Molecular And Cellular Biochemistry [P], vol 326, issue 1-2, Springer New York LLC, USA, pp. 87-95.
Trevaskis, N., Shackleford, D., Charman, W.N., Edwards, G.A., Gardin, A., Appel-Dingemanse, S., Kretz, O., Galli, B., Porter, C.J., 2009, Intestinal lymphatic transport enhances the post-prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first-pass metabolism, Pharmaceutical Research [P], vol 26, issue 6, Springer New York LLC, USA, pp. 1486-1495.
White, K.L., Nguyen, G., Charman, W.N., Edwards, G.A., Faassen, W.A.(., Porter, C.J., 2009, Lymphatic transport of methylnortestosterone undecanoate (MU) and the bioavailability of methylnortestosterone are highly sensitive to the mass of coadministered lipid after oral administration of MU, Journal Of Pharmacology And Experimental Therapeu..., vol 331, issue 2, American Society for Pharmacology and Experimental Therapeutics, USA, pp. 700-709.
Caliph, S.M., Faassen, W.A., Vogel, G.M., Porter, C.J., 2009, Oral bioavailability assessment and intestinal lymphatic transport of org 45697 and org 46035, two highly lipophilic novel immunomodulator analogues, Current Drug Delivery [P], vol 6, issue 4, Bentham Science Publishers Ltd, The Netherlands, pp. 359-366.
Kaminskas, L.M., Kota, J., McLeod, V.M., Kelly, B.D., Karellas, P., Porter, C.J., 2009, PEGylation of polylysine dendrimers improves absorption and lymphatic targeting following SC administration in rats, Journal of Controlled Release [P], vol 140, issue 2, Elsevier B.V., The Netherlands, pp. 108-116.
Kaminskas, L.M., Wu, Z., Barlow, N., Krippner, G.Y., Porter, C.J.H., 2009, Partly-PEGylated poly-L-lysine dendrimers have reduced plasma stability and circulation times compared with fully PEGylated dendrimers, Journal of Pharmaceutical Sciences [P], vol 98, issue 10, John Wiley & Sons, Inc, USA, pp. 3871-3875.
Kaminskas, L.M., Kelly, B.D., McLeod, V.M., Boyd, B.J., Krippner, G.Y., Williams, E., Porter, C.J., 2009, Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-L-lysine dendrimers, Molecular Pharmaceutics [P], vol 6, issue 4, American Chemical Society, USA, pp. 1190-1204.
Chuang, S., Velkov, T., Horne, H.J., Wielens, J., Chalmers, D.K., Porter, C.J., Scanlon, M., 2009, Probing the fibrate binding specificity of rat liver fatty acid binding protein, Journal of Medicinal Chemistry [P], vol 52, issue 17, American Chemical Society, USA, pp. 5344-5355.
Lee, K.W., Porter, C.J., Boyd, B.J., 2009, Gastric procesing is a critical determinant of the ability of lipid-based formulations to enhance the oral bioavailability of a model poorly water-soluble drug, 36th Annual Meeting & Exposition of the Controlled Release Society, 18/07-22/07/2009, Controlled Release Society, USA, p. on cd.
Boyd, B.J., Nguyen, T., Hanley, T., Porter, C.J., 2009, Non-digestible lipid-based liquid crystalline formulations, even in dispersed submicron form, provide dramatically sustained plasma concentrations for poorly water soluble drugs., 36th Annual Meeting & Exposition of the Controlled Release Society, 18/07-22/07/2009, Controlled Release Society, USA, p. on cd.
Affiliations with research centres
Drug Delivery, Disposition and Dynamics
Monash Institute of Pharmaceutical Sciences
Editorships of academic journals
Editorial board member
Journal of Pharmaceutical Sciences
Editorial board member
Journal of Pharmacy and Pharmacology
Editorial board member
Pharmaceutical Research
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