BMS2047_05_Factors that affect ADME_2023 - Copy.pdf
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BMS2047: Factors that affect drug efficacy Dr Sarah Bailey [email protected] Student feedback and consultation Thursday 27/04/23 13.00 – 14.00 Friday 05/05/23 13.00 – 14.00 Click here for other weeks 27AY04 Learning Outcomes Compare the intrinsic and extrinsic factors that can impact upon ho...
BMS2047: Factors that affect drug efficacy Dr Sarah Bailey [email protected] Student feedback and consultation Thursday 27/04/23 13.00 – 14.00 Friday 05/05/23 13.00 – 14.00 Click here for other weeks 27AY04 Learning Outcomes Compare the intrinsic and extrinsic factors that can impact upon how a drug interacts with the body Explain the rationale behind steps that can be taken to reduce the risk of adverse effects or loss of efficacy in a drug Discuss the potential (and current limitations) of personalised medicine Drug Polypharmacy Lecture bite 1 What do we need to know? Cellular effects Changes in metabolism enzymes Tissue effects Adapted from Holohan (2013) Nature Reviews in Cancer Environmental Factors - Drug:Drug Interactions Humans are exposed to thousands of different chemicals every day They may interact/compete for biological systems Perpetrators and victim drugs Pharmaceutical interactions Induction: NNTIs and rifampicin Inhibition: Gemfibrozil and simvastatin ‘consumer drug’-drug interactions Induction: St John’s Wort and warfarin Inhibition: Ecstasy and NNTIs Foodstuff-drug interactions Grapefruit juice and terfenadine Important when dose/regime setting Intrinsic factors: Genetics Mutation Errors in copying DNA If in germ line, can be passed on Migration Exchange of DNA with neighbours Founder populations Random Drift Small populations ‘Throw the dice’ Selection Advantage of one allele over other ‘Biological Fitness’ Drug transporters: P-Glycoprotein (Pgp) First defence of body and pumps drugs BACK into G.I.Tract Accounts for 17% of variation in oral clearance of Cyclosporin A Drug transporters: P-Glycoprotein (Pgp) First defence of body and pumps drugs BACK into G.I.Tract Accounts for 17% of variation in oral clearance of Cyclosporin A Khan et al., (2015) Asian Pac J Cancer Prev. 16(16):6831-6839 Summary It is easy to make a drug with a pharmacological action It is harder to get it into a form that will be taken up easily (and get to the target tissue!) It easy to predict what will happen to a ‘perfect’ person It is much harder to predict what will happen in theaverage Joe (or Joanna) It is MUCH MUCH harder to predict what will happen in a population of Joe’s and Joanna’s ADME: Examples of Drug:Drug interactions Lecture bite 2 – Beware of warfarin! Recap: Drug metabolising Enzymes & transporters Yoshida et al. (2013) Annu. Rev. Pharmacol. Toxicol. Drug metabolising Enzymes: CYP3A4 Interactions Dresser et al (2000) Clin Pharmacokinet 38 (1): 41-57 Warfarin Warfarin has a narrow therapeutic window Metabolised by may different enzymes BUT most important is production of S-warfarin to 7 hydroxyl Swarfarin by CYP2C9 Warfarin Metabolism Other substrates for CYP2C9 include fluvoxamine Carbamazepine and Clozapine REDUCE effect of warfarin by increasing expression of CYP4A4 and CYP1A2 respectively Prolonged action caused by CYP2C9 inhibitors gemfibrozil, fluorouracil and amiodarone Warfarin: Friend or foe in polypharmacy? Other sources of interactions Lecture bite 3 Drug Transporters Zamek-Gliszczynski et al. (2014) Drug Metab Dispos 42:650-664 Drug transporters: PgP St Johns wort is an inducer of PgP Drug Han (2011) Arch Pharm Res Drug transporters: PgP St Johns wort is an inducer of PgP Drug Han (2011) Arch Pharm Res Drug transporters: PgP St Johns wort is an inducer of PgP Drug Han (2011) Arch Pharm Res Food items: Grapefruit Juice IA Drug IA X Inhibitor of intestinal CYP3A4 AND P-gp Han (2011) Arch Pharm Res Food items: Grapefruit Juice IA Drug IA Drug X Inhibitor of intestinal CYP3A4 AND P-gp IA IA Drug IA Drug = inactive drug IA Drug X Han (2011) Arch Pharm Res Drug metabolites Upon phase II metabolism Gemfibrozil becomes a potent inhibitor of CYP2C8. Morphine, cerivastatin, repaglinide, rosiglitazone, pacalitaxel and pioglitazone are CP2C8 substrates Genetics: Tacrolimus is an immune suppressive used in kidney and liver transplant patients. Verapamil = PgP inhibitor References GENERAL: Rang & Dales Pharmacology (2016) 8th Edition, Elsevier. Neal (2016) Medical Pharmacology at a Glance 8th Edn Plant, N.J. (2003) Molecular Toxicology 1st Edition Gibson G.G., & Skett, P. (2001) Introduction to Drug metabolism 3rd Edition Feedback and Assessment questions in week 11 Practice MCQs on Surreylearn Discussion board questions Student feedback and consultation Friday 07/04/22 11.00 – 12.00 Thursday 05/05/21 11.30 – 12.30 Click here for other weeks References OTHERS (For additional reading): Dresser GK, Spence JD, Bailey DG. 2000) Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. Clin Pharmacokinet 38 (1): 41-57 Han, H.K. (2011) Role of transporters in drug interactions. Arch Pharm Res 34(11): 1865-1877 Khan, M., et al. (2015) Enhancing Anticancer Drug Activity in Multidrug Resistant Tumors by Modulating P-Glycoprotein with Dietary Nutraceuticals. Asian Pac J Cancer Prev, 16 (16), 6831-6839 Kunjachan, S., Rychlik, B., Storm, G., Kiessling, F., and Lammers, T. (2013) Multidrug resistance: Physiological principles and nanomedical solutions. Adv Drug Deliv Rev. 65(1314):1852-1865 Plant, N.J., and Gibson, G.G. (2003) Evaluation of the toxicological relevance of CYP3A4 induction. Curr. Op. Drug Disc. and Dev. 6: 50-56 References Holohan, C., Van Schaeybroeck, S., Longley, D.B., & Johnston, P.G. (2013) Cancer drug resistance: an evolving paradigm. Nature Reviews Cancer 13: 714–726 Rauch, A., Nolan, D., Martin, A., McKinnon, E., Almeida, C., Mallal, S. (2006) Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis. 43(1):99-102. Sivasubramanian, G., Frempong-Manso, E., & MacArthur, R.D. (2010) Abacavir/lamivudine combination in the treatment of HIV: a review. Ther Clin Risk Manag. 6: 83–94. The UK Collaborative HIV Cohort Study Steering Committee.(2013) HLA B∗5701 status, disease progression, and response to antiretroviral therapy. AIDS 27(16): 2587–2592. Yoshida K, Maeda K, Sugiyama Y. (2013) Hepatic and intestinal drug transporters: prediction of pharmacokinetic effects caused by drug-drug interactions and genetic polymorphisms Annu. Rev. Pharmacol. Toxicol. 53:581-612
