Pharmacokinetics - Drug Metabolism (Biotransformation): Download PDF, Notes, and PPT
Dive into the intricate process of Pharmacokinetics focusing on Drug Metabolism, also known as biotransformation. This downloadable PDF provides a detailed examination of how the body chemically alters drugs, primarily to facilitate their excretion. Access comprehensive notes and related PowerPoint presentations (PPTs) covering Phase I (functionalization) and Phase II (conjugation) reactions, the crucial role of enzyme systems like Cytochrome P450 (CYP450), and factors influencing metabolic rates. This resource is vital for students of pharmacology, medicine, and pharmacy.
Our PDF elucidates concepts such as enzyme induction, enzyme inhibition, first-pass metabolism, and genetic polymorphisms affecting drug metabolism. Download now to understand how biotransformation impacts drug activity, toxicity, and duration of action, which is essential for optimizing drug therapy and avoiding adverse drug interactions.
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Pharmacokinetics: The Chemical Transformation - Drug Metabolism (Biotransformation)
Drug metabolism, also known as biotransformation, is a critical component of pharmacokinetics (ADME) that involves the chemical alteration of drugs within the body. The primary goal of metabolism is to convert lipophilic (fat-soluble) drugs, which are poorly excreted by the kidneys, into more polar, water-soluble metabolites that can be readily eliminated in urine or bile. This process often, but not always, leads to the inactivation of the drug. The liver is the principal site of drug metabolism, although other tissues like the gut wall, lungs, kidneys, skin, and plasma also possess metabolic capabilities. This PDF on "Pharmacokinetics metabolism" provides an essential overview of this complex process.
Consequences of Drug Metabolism
Biotransformation can lead to several outcomes:
- Inactivation: Most commonly, metabolism converts an active drug into an inactive metabolite (e.g., phenytoin to inactive p-hydroxy-phenytoin). This is the primary mechanism for terminating drug action.
- Activation of Prodrugs: Some drugs are administered as inactive or less active prodrugs and are metabolically converted to their active forms in the body (e.g., enalapril to enalaprilat, levodopa to dopamine).
- Formation of Active Metabolites: An active drug may be converted to another active metabolite, which can contribute to the therapeutic effect or toxicity, and may have a longer half-life than the parent drug (e.g., diazepam to oxazepam, codeine to morphine).
- Formation of Toxic Metabolites: In some cases, metabolism can lead to the formation of reactive or toxic metabolites (e.g., paracetamol (acetaminophen) metabolism can produce NAPQI, a hepatotoxic metabolite, if not detoxified by glutathione).
- Altered Pharmacological Activity: Metabolism might change the type of pharmacological activity.
Phases of Drug Metabolism
Drug metabolism typically occurs in two phases, often sequentially, although some drugs may undergo only Phase I or only Phase II reactions, or bypass Phase I altogether.
- Phase I Reactions (Functionalization Reactions):
These reactions introduce or unmask a functional group (e.g., -OH, -NH2, -SH, -COOH) on the parent drug molecule, usually making it more polar and providing a site for subsequent Phase II reactions. Phase I reactions generally involve:
- Oxidation: The most common type of Phase I reaction, primarily catalyzed by the Cytochrome P450 (CYP450) enzyme system located in the smooth endoplasmic reticulum of liver cells (microsomal enzymes). Other oxidative enzymes include alcohol dehydrogenase and monoamine oxidase. Examples include hydroxylation, dealkylation, deamination, sulfoxidation.
- Reduction: Less common than oxidation, catalyzed by reductases (e.g., nitro reduction of chloramphenicol).
- Hydrolysis: Cleavage of drug molecules by the addition of water, catalyzed by esterases, amidases, or peptidases. Occurs in plasma, liver, and other tissues (e.g., hydrolysis of procaine by plasma esterases, aspirin by esterases).
Metabolites from Phase I reactions may be sufficiently polar to be excreted, or they may proceed to Phase II.
- Phase II Reactions (Conjugation Reactions):
These are synthetic reactions where an endogenous substance (e.g., glucuronic acid, sulfate, glutathione, acetate, amino acids) is conjugated (covalently attached) to the drug or its Phase I metabolite. This process usually results in a larger, more water-soluble, and pharmacologically inactive conjugate that is readily excreted in urine or bile. Phase II enzymes are mainly transferases.
- Glucuronidation: Most common conjugation reaction, catalyzed by UDP-glucuronosyltransferases (UGTs). Attaches glucuronic acid (derived from glucose) to drugs with -OH, -COOH, -NH2, or -SH groups (e.g., morphine, paracetamol).
- Sulfation: Conjugation with sulfate, catalyzed by sulfotransferases (SULTs) (e.g., paracetamol, steroids).
- Acetylation: Transfer of an acetyl group from acetyl-CoA, catalyzed by N-acetyltransferases (NATs) (e.g., isoniazid, sulfonamides). Genetic polymorphisms in NATs lead to "fast" and "slow" acetylator phenotypes.
- Methylation: Addition of a methyl group, catalyzed by methyltransferases (e.g., dopamine, histamine).
- Glutathione Conjugation: Important for detoxifying reactive electrophilic metabolites, catalyzed by glutathione S-transferases (GSTs) (e.g., detoxification of NAPQI from paracetamol).
- Amino Acid Conjugation: Conjugation with amino acids like glycine or glutamine (e.g., salicylic acid).
Cytochrome P450 (CYP450) Enzyme System
The CYP450 supergene family of enzymes is the most important enzyme system involved in Phase I drug metabolism. These are heme-containing monooxygenases. There are many isoforms (e.g., CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2), each with specificity for certain substrates (drugs). Genetic variations (polymorphisms) in CYP genes are a major cause of interindividual differences in drug response and toxicity (pharmacogenetics).
Factors Affecting Drug Metabolism
- Genetic Factors (Pharmacogenetics): Polymorphisms in metabolic enzymes (e.g., CYP2D6, CYP2C19, NAT2) can lead to poor, intermediate, extensive, or ultrarapid metabolizer phenotypes, significantly affecting drug efficacy and toxicity.
- Age:
- Neonates and Infants: Have immature metabolic enzyme systems, leading to slower metabolism and increased sensitivity to some drugs.
- Elderly: Often have reduced liver mass, blood flow, and enzyme activity, leading to slower metabolism and prolonged drug effects.
- Disease States: Liver diseases (e.g., cirrhosis, hepatitis) can significantly impair metabolic capacity. Cardiovascular diseases can reduce liver blood flow. Thyroid dysfunction can also alter metabolism.
- Nutrition: Malnutrition can decrease enzyme levels and cofactors. Specific dietary components can induce or inhibit enzymes.
- Environmental Factors: Exposure to certain chemicals (e.g., cigarette smoke, pesticides, industrial pollutants) can induce or inhibit metabolic enzymes.
- Drug Interactions:
- Enzyme Induction: Some drugs (e.g., rifampicin, carbamazepine, phenobarbital, St. John's Wort) can increase the synthesis of CYP450 enzymes, leading to faster metabolism of themselves (autoinduction) or other co-administered drugs that are substrates for the induced enzyme. This can result in decreased efficacy or therapeutic failure.
- Enzyme Inhibition: Some drugs (e.g., cimetidine, ketoconazole, erythromycin, grapefruit juice) can inhibit the activity of CYP450 enzymes, leading to slower metabolism of co-administered drugs that are substrates for the inhibited enzyme. This can result in increased plasma concentrations, prolonged effects, and increased risk of toxicity.
- First-Pass Metabolism (Presystemic Metabolism): Orally administered drugs, after absorption from the GI tract, pass through the liver via the portal vein before reaching systemic circulation. If a drug is rapidly metabolized in the liver or gut wall during this first pass, its bioavailability is significantly reduced. This is a major consideration for oral drug dosing.
Understanding drug metabolism is crucial for rational drug therapy. It helps in predicting drug interactions, individualizing doses based on patient factors (like genetics or organ function), and developing new drugs with improved metabolic profiles. This PDF provides foundational knowledge for these critical concepts in pharmacology.
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