Pharmacokinetics (Part 3) - University of Baghdad 2024-2025 PDF

University of Baghdad College of Medicine 2024-2025 Title: PHARMACOKINETICS (part 3) Grade: 2nd Module: Principles of Pharmacology (PP) Speaker: Dr. Zainab Al-Jassim Date: 16 /10 / 2024  Metabolism...

University of Baghdad College of Medicine 2024-2025 Title: PHARMACOKINETICS (part 3) Grade: 2nd Module: Principles of Pharmacology (PP) Speaker: Dr. Zainab Al-Jassim Date: 16 /10 / 2024  Metabolism More Polar S drug , Sin sid , ja Metabolism into energy. is the chemical reactions in the body's cells that change food 3 Drug metabolism is the term used to describe the biotransformation of prog[ pharmaceutical substances in the body so that they can be eliminated more easily. The majority of metabolic processes that involve drugs occur in the liver, as the enzymes that facilitate the reactions are concentrated there. The metabolites usually have a lower pharmacologic activity than the parent compound. Metabolism leads to production of products with increased polarity, which allows the drug to be eliminated.  All drugs are eventually eliminated from the body. They may be eliminated after being chemically altered (metabolized), or they may be eliminated intact.  Most drugs, particularly water-soluble drugs and their metabolites, are eliminated largely by the kidneys in urine. Therefore, drug dosing depends largely on kidney function. Some drugs are eliminated by excretion in the bile.  Some drugs are excreted also in saliva, sweat, breast milk, and even exhaled air. Most are excreted in small amounts.  Most drugs are eliminated according to first-order kinetics, in which the rate of elimination is directly proportional to the serum drug concentration. A few substances are eliminated by zero-order elimination kinetics, which are eliminated at a fixed rate regardless of drug concentration. Examples are Ethanol, Phenytoin, Salicylates, Cisplatin, Fluoxetin, Omeprazol, also aspirin in high doses, are eliminated according to zero-order or nonlinear kinetics. Kinetics of Metabolism: 1. First-order kinetics:  Metabolism catalyzed by enzymes.  The rate of drug metabolism and elimination is directly proportional to the concentration of free drug.  a constant fraction of drug is metabolized per unit of time (that is, with each half-life, the concentration decreases by 50%).  For drugs that follow first-order kinetic, t1/2 is independent of drug concentration.  Do not have saturable metabolism at standard doses. In overdoses, saturable metabolism can occur for many drugs. 2. Zero-order kinetics: Zero-order kinetics define processes that occur at a constant rate per unit of time. The rate of elimination remain constant irrespective of drug concentration. e.g. ethyl alcohol (5 mg/ min). Zero order kinetics are rare elimination mechanisms and are saturable (Saturation of metabolism occurs when enzymes involved in the metabolism of drugs have reached capacity.) How does the liver metabolize drugs? Within the liver, there are an important group of enzymes called cytochrome P450 (CYP450). Also, they are located in most cells, but primarily in the liver and GI tract. In the liver, they’re found in the hepatic smooth endoplasmic reticulum within the hepatocytes. The family of enzymes is broken down into subcategories – important examples are CYP450 3A4, 2D6, 2C19 and 2C9. These enzymes can be inhibited or induced by drugs. Inducers means it may increase drug metabolism which can decrease drug activity if the metabolite is inactive or increase activity if the metabolite is active. Inhibitors may lead to higher levels and/or greater potential of drugs. Also, these enzymes are subjected to genetic variations between individuals of different racial groups and so altered metabolism of drugs. Common Cytochrome P450 Interactions: Isoenzyme Inhibitor Inducer Substrate Prodrug Substrate CYP3A4 Grapefruit juice Phenobarbital, Phenytoin, Clarithromycin Clarithromycin Rifampicin, Erythromycin Erythromycin St. John’s Wort Warfarin Diltiazem Glucocorticoids Some statins (e.g. Itraconazole Simvastatin) Fluconazole Ritonavir verapamil Cimetidine CYP2D6 Fluoxetine Rifampicin B-blockers Codeine Paroxetine TCAs Tamoxifen Bupropion Tramadol Quinidine Codeine Amiodarone CYP2C19 Lansoprazole omeprazole Rifampicin Warfarin Clopidogrel fluvoxamine Carbamazepine Diazepam Phenytoin CYP2C9 Miconazole Rifampicin Warfarin Losartan Fluconazole Carbamazepine NSAIDs CYP2C8 Cimetidine Phenobarbital Diazepam Rifampicin CYP1A2 Cimetidine Cigarette smoke Theophylline Ciprofloxacin CYP2E1 Disulfiram Ethanol Ethanol Isoniazid Halothane Isoflurane Proportion of drugs metabolized by different CYPs Genetical variations: Genetic variations can lead to altered CYP450 polymorphisms and so altered metabolism of drugs. Examples:  CYP450 2D6 enzyme polymorphisms, Some people are poor metabolizers. Others are rapid or ultra-rapid metabolizers. Codeine (an opioid pain reliever) is a prodrug which means it must be metabolized into its active form (morphine) to work. This occurs via the CYP450 2D6 enzyme. Poor metabolizers may not metabolize codeine effectively and may be resistant to its effects. Ultra-rapid metabolizers may be the opposite and experience large conversion to morphine rendering them sensitive to the drug.  Clopidogrel (antiplatelet) carries a warning that patients who are poor CYP2C19 metabolizers have a higher incidence of cardiovascular events (e.g. stroke or myocardial infarction) when taking this drug. Clopidogrel is a prodrug, and CYP2C19 activity is required to convert it to the active metabolite. Genotypes of the patient are usually classified into the following predicted phenotypes according to the metabolic rate: UM-Ultra-rapid metabolizer: the patients with substantially increased metabolic activity. EM-Extensive metabolizer: the normal metabolic activity. IM-Intermediate metabolizer: the patients with reduced metabolic activity PM-Poor metabolizer: the patients with little to no functional metabolic activity.  Reactions of drug metabolism The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents are first metabolized into more polar (hydrophilic) substances in the liver via two general sets of reactions, called phase I and phase II : Phase I: (Oxidation, reduction or hydrolysis)  Occurs in the liver  most frequently involved the cytochrome P450 system.  Convert lipophilic drugs into more polar molecules by introducing or unmasking a polar functional group, such as –OH or –NH2.  usually involve reduction, oxidation, or hydrolysis.  may increase, decrease, or have no effect on pharmacologic activity.  Phase I reactions not involving the P450 system include amine oxidation (Ex., oxidation of catecholamines or histamine), alcohol dehydrogenation (Ex., ethanol oxidation), esterases , and hydrolysis. Phase II: (Conjugation, glucuronidation, acetylation etc.) o Occurs in the liver and kidneys o Phase II drug metabolizing enzymes are mainly transferases. o If the metabolite from phase I metabolism is sufficiently polar, it can be excreted by the kidneys. However, many phase I metabolites are still too lipophilic to be excreted. A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are often therapeutically inactive. The major phase II enzymes: UDP-glucuronosyltransferases, sulfotransferases, N- acetyltransferases, glutathione S-transferases and methyltransferases (mainly thiopurine S- methyl transferase and catechol O-methyl transferase).