BMS2047 Drug Metabolism - ADME Basics (2023) PDF

BMS2047: Drug Metabolism – ADME basics Dr Sarah Bailey [email protected] 27AY04 Student feedback and consultation Thursday 30/03/23 14.00 – 15.00 Thursday 27/04/23 13.00-14.00 Click here for other weeks Or book an appointment if these hours do not work for you https://calendly.com/sgbailey/15m...

BMS2047: Drug Metabolism – ADME basics Dr Sarah Bailey [email protected] 27AY04 Student feedback and consultation Thursday 30/03/23 14.00 – 15.00 Thursday 27/04/23 13.00-14.00 Click here for other weeks Or book an appointment if these hours do not work for you https://calendly.com/sgbailey/15min Learning Outcomes       Discuss the pros and cons of different routes of administration for drugs Explain how drugs cross the biological membrane by different routes and how this influences drug formulation Describe why basic/acidic groups are useful for improving drug absorption Apply the theory of lipid solubility to explain effects on drug absorption/efficacy Be able to apply the theory of VD and the four factors that affect drug distribution to identify the best therapy. Implement knowledge of drug design modification to improve penetration of target tissue Introduction to ADME What do we need to know? Cellular effects Changes in metabolism enzymes Tissue effects Adapted from Holohan (2013) Nature Reviews in Cancer ADME – who cares? Drug companies (developers):  Too many drugs fail at clinical trials  Need to develop better second generation drugs  Need to develop “niche-population” drugs Doctors (prescribers):  Judge the risk-benefit for a drug  Communication to patients  Due to interest RISK MANAGEMENT Vs RISK PERCEPTION Fate of the drug in the body Figure 8.8 Rang & Dales Pharmacology (2016) 8th Edition Solubility and dissolution  Solubility is the concentration of a saturated solution of drug at a specified temperature and pressure.  A drug must be in solution (molecular form) for absorption to take place  Dissolution is the rate at which a drug goes into solution Adjacent to the dissolving surface is a saturated layer (diffusion layer). Drug must diffuse through this layer before it is released into the medium Oral Administration  Easy for patient = high compliance  Ionisation affects:  rate at which drugs permeate membranes  ratio of ionised to un-ionised drug is governed by the pKa of the drug and the pH of that compartment  Drug must move from GI Tract into plasma pH and ease of distribution  steady-state distribution of drug molecules between aqueous compartments, when a pH difference exists between them.  Slightly acidic/basic drugs are absorbed well Figure 8.3 Rang & Dales Pharmacology (2016) 8th Edition pH and ease of distribution  steady-state distribution of drug molecules between aqueous compartments, when a pH difference exists between them.  Slightly acidic/basic drugs are absorbed well Figure 8.3 Rang & Dales Pharmacology (2016) 8th Edition Some common Drugs: Figure 8.3 Rang & Dales Pharmacology (2016) 8th Edition Key issues/principles to consider  Urinary acidification accelerates excretion of weak bases and retards that of weak acids  Urinary alkalinisation has the opposite effects: it reduces excretion of weak bases and increases excretion of weak acids.  Changing compartment pH can have (unwanted) side effects:  Increasing plasma pH causes weakly acidic drugs to be extracted from the CNS into the plasma.  Reducing plasma pH causes weakly acidic drugs to become concentrated in the CNS, increasing their neurotoxicity Lipid solubility Lipid solubility  Absorption of non-polar forms are favoured  Lipid solubility of non-polar form is also important  Physical movement of compound into and out of the membrane K=  Concentration in lipid solvent Concentration in water solvent Will affect the rate and/or amount of absorption and therefore the time to onset of clinical effect Lipid solubility Figure 8.2 Rang & Dales Pharmacology (2016) 8th Edition Other ways of cell entry & getting to the target Lecture Bite 3 Role of Active Transport  Transport of polar chemicals across membranes  Substrates may be endogenous or exogenous  Implications of drug transport:  Control entry of chemicals to the body  Control disposition within the body  Impact on pharmacokinetics  Impact on clinical efficacy Transporters are the front line against toxicity Drug Transporters and Absorption Defend the body \ Drug Transporters and Absorption Expression levels can change rapidly. Exposure to an endogenous or exogenous ligand can lead to an increase in transporter expression Can result in drug resistance e.g. cancer therapy Can result in drug-drug interactions e.g. rifampicin and cyclosporine Figure 8.5 Rang & Dales Pharmacology (2016) 8th Edition Drug distribution Distribution  Main factors that affect distribution from plasma to the rest of the body:  Plasma binding protein  Interaction with adipose tissue  Blood flow to tissues  Membrane barriers Drug Distribution Volume of distribution (VD) = volume that would contain the total body content (Q) of the drug at an equal concentration to plasma (CP). VD gives a measure of how well the drug is distributed throughout the body Dose = 10mg Cp = 20mg/L Apparent volume 500ml Dose = 10mg Cp = 2mg/L Apparent volume 500ml VD = Q Cp Plasma binding protein  Albumin is the main plasma protein in blood  Role is to maintain colloidal osmotic pressure of blood  High binding capacity for H2O, Ca2+, Na+, K+, fatty acids, hormones and drugs  Can bind to both acidic and basic drugs (has acidic and basic amino acids) FREE DRUG BOUND DRUG Binding is reversible TARGET ORGAN Binding results in: ✓Reduced elimination ✓Reduced pharmacological action ✓Potential displacement of other drugs already bound Must alter the treatment regime to accommodate this Phase I Drug Metabolism Lecture Bite 4 Learning Outcomes  Explain the requirement for metabolism to remove lipophilic drugs  Describe how the balance of Phase I and II metabolism affects:  the duration of a therapeutic window for a drug  how the two phases interact to aid removal of drugs  Integrate the knowledge above to explain how metabolism often leads to activation and then deactivation of drugs, considering:  Implications for toxicity  Implications for efficacy  Describe the main routes of excretion and apply reasoning as to why a particular route is utilised.  Link and explain the role of excretion on drug action, predicting how this and other factors can be modified to improve patient response. Why do we metabolise drugs? The body naturally acts to remove chemical (endogenous or exogenous)  Main routes of removal are urine and faeces (i.e. hydrophilic / polar)  Most drugs are lipophilic / non-polar  Must be made hydrophilic / polar before they can be excreted  Metabolism is the process of converting chemicals to more polar metabolites  Primarily in liver, but can occur in all organs Excreted in urine/faeces DRUG (D) Phase I D–OH Phase II D–OX Polarity of drug / metabolite Drug Metabolism Overview Phase I Metabolism  Functionalisation reactions  Create or reveal a ‘handle’ for Phase 2 metabolism  Oxidation  Reduction NADPH + H+  Hydrolysis  Oxidation the most important  Catalysed by a super-family Cytochrome P450s D + O2 NADP+ D-OH + H2O of enzymes called the Phase I Metabolism  Functionalisation reactions  Create or reveal a ‘handle’ for Phase 2 metabolism  Oxidation  Reduction NADPH + H+  Hydrolysis  Oxidation the most important  Catalysed by a super-family Cytochrome P450s D + O2 NADP+ D-OH + H2O of enzymes called the Cytochrome P450s  Present in species from bacteria to mammals ❖ 57 known human P450s  Many P450s are inducible by compounds that are substrates  For drug metabolism, families 1-3 are the most important ❖ CYP1: Polycyclic Aromatic Hydrocarbons (PAHs) ❖ CYP2: Many drugs ❖ CYP3: >50% of drugs in clinical use that are oxidised  Remember CYPs have endogenous substrates as well! CYP3A4 – an example Phase I enzyme Most abundant P450 in human liver  >50% of drugs in clinical usage today, that are oxidised, are substrates  Very wide substrate specificity Rifampicin Metyrapone Phase II Drug Metabolism Lecture Bite 5 Phase II Metabolism  Addition of conjugates to increase hydrophilicity o Glucuronic Acid o Sulphate o Amino acids o Glutathione (Glu-Gly-Cys) o Acetylation  Multiple different enzymes  Inducible  Drug metabolite should now be polar enough to be excreted via urine/faeces Types of Phase II metabolism Glucuronidation  Base unit glucose-1-phosphate  Ubiquitous and highly expressed (exception cat)  High energy conjugate  Important in enterohepatic recirculation Types of Phase II metabolism Glucuronidation  Base unit glucose-1-phosphate  Ubiquitous and highly expressed (exception cat)  High energy conjugate  Important in enterohepatic recirculation Sulphation Sulphation  Similar substrate profile as glucuronidation  High energy conjugate  Inorganic sulphate may limit  Large variability in species/tissue expression [substrate] Glucuronidation Types of Phase II metabolism Glutathione conjugation  GSH (Tripeptide: Glu-Gly-Cys)  Low energy conjugate ▪ Halides and epoxides  Ubiquitous with a good conjugate pool (mM) ▪ Both cytosolic and membrane-bound variants ▪ All species have good GST systems ▪ Depletion of GSH pool leads to toxicity  Biological Hoover  Production of GST conjugates may be a marker of toxicity Multiple possibilities Metabolism can occur at multiple sites within one molecule:  Metabolism can ‘activate’ drugs  The balance determines the outcome  Cyclophosphamide – activated in Liver so no adverse GIT effects Rodriguez-Antona and Ingelman-Sundberg (2006) Oncogene An Example Summary Excretion Lecture bite 6 An overview of drug excretion  Final clearance of drugs from the body  Also, final chance to KEEP drugs IN the body  Metabolism  Major Routes of Excretion Kidney Liver G.I.Tract  Minor Routes of Excretion Lungs Sweat Lacrimal fluid Milk Renal Excretion Overall elimination is the net effect of:  Glomerular filtration  Tubular secretion  Tubular re-absorption These processes are both PASSIVE and ACTIVE Multiple factors affect the rate of elimination  Integrity of kidney  Molecule size  Urine flow  Urine pH  Other compounds that are being excreted Click here for link back to Dr Jabrs’ Renal physiology lecture content. Glomerular Filtration  Passive process  Dependent upon hydrostatic  pressure gradient Size cut-off  Small molecules (most drugs)  Removes plasma proteins  Hence filtration is dependent upon free drug in plasma only  Changes in the fraction of unbound drug may change the rate of renal elimination  Changes in the amount of plasma protein  Displacement from plasma protein by other drugs Drug Transporters and Excretion Expression levels can change rapidly. Exposure to an endogenous or exogenous ligand can lead to an increase in transporter expression. See slides in last lecture for absorption, they also apply here. Effects on the duration of a drug being maintained in the “therapeutic window” Liver Excretion  Generally the excretion route for drugs not excreted via kidney  Large (Mr >300): Often route for glucuronide conjugate  Secretion into bile and then intestine Click here for to my liver content. Excretion and the liver NUTRIENT RICH  First pass metabolism HEPATIC sinusoids HEP Adapted from Tortora & Derrickson (2017) Principles of Anatomy and Physiology, 15th Edition, Wiley, UK. NUTRIENT RICH HEPATIC VEIN HEPATIC ARTERY ↑NUTRIENTS PORTAL VEIN AORTA Can occur before a drug even gets into the systemic blood supply VENA CAVA  Liver Excretion can be transporter mediated Enterohepatic Recirculation Reabsorption can take place for liver excretion as well as kidney route ADME summary: To post on the discussion board click here 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  Additional learning activities on Surreylearn  Practice MCQs on Surreylearn  Discussion board questions Student feedback and consultation Thursday 30/03/23 14.00 – 15.00 Thursday 27/04/23 13.00-14.00 Click here for other weeks References OTHERS (For additional reading): Allocati et al.(2018) Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases. Oncogenesis 7:8 International Transporter Consortium (2010) Membrane transporters in drug development. Nat Rev Drug Discov. 9(3):215-36. Giacomini KM et al. (2010) Membrane transporters in drug development: Nature Reviews Drug Discovery 9, 215-236. Simic, T., et al. (2009) Glutathione S-transferases in kidney and urinary bladder tumors. Nat. Rev. Urol. 6:281–289 Rivory, L.P., Slaviero, K.A., Hoskins, J.M., and Clarke, S.J. (2001) The Erythromycin Breath Test For the Prediction of Drug Clearance. Clinical Pharmacokinetics 40(3):151–158 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(13-14):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 Places to find more information & apply your knowledge:  Holohan, C., Van Schaeybroeck, S., Longley, D.B., Johnston, P.G. (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 13(10):714-26.  Zamek-Gliszczynski, M.J., Chu, X., Polli, J.W., Paine, M.F., and Galetin A. (2014) Understanding the Transport Properties of Metabolites: Case Studies and Considerations for Drug Development. Drug Metabolism and Disposition 42 (4) 650664.