BMS2047 Factors Affecting ADME 2023 PDF

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