Pharmacokinetics Lecture 2: Drug Distribution & Metabolism

PHARMACOKINETICS Lecture 2: Principles of Distribution & Metabolism Learning Objectives – After studying this subject, you should be able to: ❑ Describe the drug and tissue factors affecting distribution ❑ Explain the concept of apparent volume of distribution and how it relates to drug properties ❑...

PHARMACOKINETICS Lecture 2: Principles of Distribution & Metabolism Learning Objectives – After studying this subject, you should be able to: ❑ Describe the drug and tissue factors affecting distribution ❑ Explain the concept of apparent volume of distribution and how it relates to drug properties ❑ Explain the importance of drug metabolism and differentiate between phase I and phase II biotransformation ❑ Describe the role of cytochrome p450 system in drug-drug interactions N ADME: Distribution ri a ▪ Distribution: the movement of drugs from the systemic circulation to various tissue compartments • The initial rapid fall in plasma concentration is mainly due to the quickly mm I_ forming drug equilibrium between plasma & body compartments ✑ Distribution phase • If The later slow decline in plasma concentration is mainly due to elimination mechanisms to remove the drug from body ✑ Elimination phase If 11/1/2023 Najla Taslim, PhD 27 Editing Distribution & Drug Plasma Concentration in various Body compartments FYI 11/1/2023 Lippincott Illustrated Reviews: Pharmacology (7th edition) 28 Factors Influencing Distribution to Target Tissue ▪ Determined by the ability of drugs: o To exit the vascular system: - Lipid solubility of the drug [↑distribution] - Protein binding (e.g. Albumin) [↓distribution] o To reach the tissue: diddtion organs m.gef6oo he wish Irate a wee - Blood flow to the organ [↑distribution] - Biological barriers (e.g. Blood-brain barrier/BBB) 6 [↓distribution] f ii FI.it iÉ ÉE or protierbinding dist I Note: Distribution follows similar principles of absorption, with the drug moving between various compartments in the body after its absorption 11/1/2023 Najla Taslim, PhD 29 Editing Plasma Protein Binding (“Blood Distribution”) • Drug is present in blood as free or bound to plasma proteins o Free/bound equilibrium is dependent on drug binding affinity to plasma proteins o Free fraction is responsible for drug effects. Why? (Hint: Receptor selectivity) o Bound fraction serves as drug reservoir • Two major plasma proteins bind to drugs o Albumin: binds mainly acidic and neutral drugs EEE.ITdin É o Alpha-1 acidic glycoprotein: binds mainly basic drugs plasma ption A Birdman acidic Neutral Effingham Basisdrugs Najla Taslim, PhD 30 Editing g Protein binding & drug distribution Movement across typical capillary Protein binding can • Prevent tissue distribution • Lead to drug-drug interaction when 2 drugs compete for the same binding site. • Serious consequences can occur. 11/1/2023 prox 31 Najla Taslim, PhD Blood brain barrier [BBB] impedes the distribution of most drugs to the CNS However, lipid soluble drugs can easily cross the BBB 3 Brody’s Human Pharmacology: Molecular to Clinical (5th edition) 32 Apparent Volume of Distribution (Vd) Volume of distribution (Vd): A hypothetical volume in the body that contains drug other than plasma. Ajw Vd = Amount of drug in the body (mg) = (L) Plasma drug concentration (mg/L) Dose y am Ud Am The plasma a 9 drug conc Same amount of drug given in both cases Progress in Medicinal Chemistry, Volume 61 ISSN 0079-6468 https://doi.org/10.1016/bs.pmch.2022.04.002 11/1/2023 33 Example Will a drug strongly bound to plasma proteins likely have a large or small Vd? e.g. Actual plasma volume = 5L IV administered drug = 100mg Plasma concentration = 18mg/L 1L plasma Answer: Vd = 100 mg = 5.6 L (small Vd) 18 mg/L Will a very lipophilic drug likely have a large or a small Vd? e.g. Actual plasma volume = 5L o IV administered drug = 100mg Plasma concentration = 3mg/L Answer: Vd = 100 mg = 33.3 L (large Vd) 3 mg/L 1L plasma Brody’s Human Pharmacology: Molecular to Clinical (5th edition) 34 ADME: Metabolism Importance of Drug Metabolism ❑ Lipophilic drugs are not directly excreted in urinary fluid ❑ Drug metabolism ↓ lipid solubility and increases ionization (↑ water solubility) r ❑ Essential for drug clearance and renal elimination of metabolites ❑ May activate pro-drugs (e.g. Clopidogrel activation by CYP enzymes) tf antipatieta.ws ❑ May produce active and/or toxic metabolites ❑ The primary site of drug metabolism is the liver ❑ Important area of drug-drug interactions o 11/1/2023 35 Phases (Pathways) of Drug Metabolism 2 11/1/2023 i e Lippincott Illustrated Reviews: Pharmacology (7th edition) Int. J. Mol. Sci. 2021, 22(23), 12808; https://doi.org/10.3390/ijms222312808 36 Phase I Biotransformation I - Hydrolysis Phase I –Phase Hydrolysis (in most tissues) COOH O C mm COOH O CH3 OH Esterase + HO H2O C CH - CH - NH2 CH3 • Esterases, Amidases • Add Water Across Bond • Exposes Functional Group(s) Cytochrome P450 System • Most Tissues and Plasma • Family of hemoprotein enzymes • e.g. CYP3A4, CYP3A5, CYP2D6 or • CYPs catalyze oxidation reactions • Highest concentration in the liver • Site of drug-drug interactions 11/1/2023 mm O Salicylic Acid Aspirin Phase I Biotransformation Phase I – Oxidation (mainly in liver) amphetamine OH OH cytochrome P450 O2 HO CH - CH - NH2 OH OH • Variety Substrates • Variety Reactions - Oxidation, Hydroxylation FYI • Reactive O2 • Add Functional Group Antioxidants 2020, 9(5), 454; https://doi.org/10.3390/antiox9050454 37 Phase II Biotransformation •Coupling of Group to Drug or Metabolite Conjugation Phase II Biotransformation •To Increase Water Solubility and Ionization Enhancing Renal or Biliary Excretion •Pharmacologically Inactive •PresentPhase for Endogenous Substrates II – Conjugation COOH OH + glucuronide e.g. Phase II Metabolism COOH O glucuronide 2. Sulphation Conjugate Salicylic Acid 1. Glucuronidation Salicylic Glucuronide 3. Methylation 4. Acetylation 5. Glutathione conjugation Purpose of Phase II reactions Coupling of a functional chemical group (e.g. glucuronide) to drug or metabolite to: • Increase ionization/water solubility • Enhance urinary & biliary excretion • Produce pharmacologically inactive compounds 11/1/2023 38 Example Acetaminophen/Paracetamol Biotransformation Glucoronide conj. *>90% Chemical Structures FYI *<10% Sulfate conj. Unstable metabolite *Overdose toxicity: Conjugation is saturated; GSH deple Occurs and CYP oxidation ↑↑ NAPQI production Liver toxicity Drug treatment: N-acetylcysteine (NAC) Replenishes GSH + ↑ Conjugation Reactive metabolite + Toxic 11/1/2023 (GSH) w 39 Drug-Drug Interactions CYP enzyme Induction s CYP enzyme Inhibition e Increased (↑) metabolism Decreased (↓) metabolism Result: Result: > Increased (↑) drug clearance > Decreased (↓) drug clearance > Decreased (↓) drug half-life > Increased (↑) drug half-life Examples of inducers: Examples of inhibitors: • Carbamazepine To at • Cimetidine • Phenobarbital • Ketoconazole • Phenytoin • Grapefruit juice • Rifampicin • Isoniazid (INH) nd rie.li if11/1/2023 inducer phenobarbital 0.18 6 amazepine if 4m 40 jjqffffehnaz.ie Example rel e Phenytoin 9201 Warfarin Clearance and Clot Time CYP Inducer: Phenobarbital C ➢ Decreased warfarin activity CYP Inhibitor: Cimetidine ➢ Increased warfarin activity Plasma Warfarin (ug/ml) Thrombotest (%) Warfarin Clearance and Clot Time Warfarin Clearance and Clot Time plasma warfarin ng/ml 0 10 20 Phenobarbitone Induces Several Cytochrome P450s 30 40 Phenobarbitone 3.0 2.0 2000 warfarin prothrombin time Cimetidine Inhibits Many Cytochrome P450s PT sec 1600 1200 25 23 21 19 17 800 1.0 0 Warfarin 0 8 16 24 32 40 48 56 64 72 400 Cimetidine Warfarin 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Days of Study Time (days) Courtesy of Dr. Todd Vanderah 11/1/2023 41 Practice Qs • Drug distribution to the brain is limited in normal circumstance because of the; • • • • Blood brain barrier Poor blood flow Low protein binding High polarization of drugs Answer A • If drug A inhibits the metabolism of drug B, this interaction will lead to, b b drubbitist• More toxicity by drug B • Rapid excretion of drug B • Decreased effect of drug B halflife• High metabolism of drug A drug AnswerA Najla Taslim, PhD 11/1/2023 42 Thank You Questions?