💊Medicinal Chemistry Unit 9 – Drug Metabolism and Toxicology

Key Concepts and Terminology

• Pharmacokinetics studies the absorption, distribution, metabolism, and excretion (ADME) of drugs in the body
• Pharmacodynamics examines the biochemical and physiological effects of drugs on the body and their mechanism of action
• Biotransformation is the process by which the body modifies a drug through chemical reactions, often to make it more water-soluble for easier elimination
• Phase I reactions involve oxidation, reduction, or hydrolysis of the drug, typically catalyzed by cytochrome P450 enzymes (CYPs)
• Phase II reactions involve conjugation of the drug or its metabolites with endogenous substances (glucuronic acid, sulfuric acid, acetic acid) to increase water solubility
• Bioavailability refers to the fraction of an administered dose of a drug that reaches the systemic circulation unchanged
• Half-life $(t_{1/2})$ is the time required for the concentration of a drug in the body to decrease by half
  • Determines the dosing frequency and time to reach steady-state concentrations
• Clearance is the volume of plasma cleared of a drug per unit time, reflecting the body's ability to eliminate the drug

Principles of Drug Metabolism

• Drug metabolism primarily occurs in the liver, but can also take place in other tissues (intestines, kidneys, lungs)
• The main goal of drug metabolism is to convert lipophilic compounds into more water-soluble metabolites for easier elimination from the body
• Metabolism can lead to the activation of prodrugs, which are inactive compounds that become pharmacologically active after biotransformation
  • Example: Codeine is metabolized to morphine by CYP2D6
• Metabolism can also result in the inactivation of active drugs, reducing their therapeutic effects
• Some metabolites may be pharmacologically active or toxic, contributing to the overall effects of the drug
• First-pass metabolism refers to the metabolism of a drug before it reaches the systemic circulation, which can significantly reduce its bioavailability
  • Occurs primarily in the liver and intestines
• Genetic variations in drug-metabolizing enzymes can lead to interindividual differences in drug response and toxicity

Major Metabolic Pathways

• Oxidation reactions, catalyzed by CYPs, introduce oxygen into the drug molecule or remove hydrogen atoms
  • Examples: Hydroxylation, dealkylation, deamination, sulfoxidation
• Reduction reactions, less common than oxidation, involve the addition of hydrogen atoms or removal of oxygen
  • Examples: Ketone reduction, azo reduction, nitro reduction
• Hydrolysis reactions involve the cleavage of esters, amides, or peptide bonds by the addition of water
  • Examples: Ester hydrolysis by esterases, amide hydrolysis by amidases
• Conjugation reactions attach endogenous substances to the drug or its metabolites, increasing water solubility
  • Glucuronidation, the most common conjugation reaction, attaches glucuronic acid to the drug
  • Sulfation attaches sulfuric acid to the drug, typically at hydroxyl or amine groups
  • Acetylation attaches an acetyl group to the drug, usually at amine groups
  • Methylation attaches a methyl group to the drug, often at amine or hydroxyl groups
  • Glutathione conjugation attaches the tripeptide glutathione to the drug, important for detoxification of reactive metabolites

Enzymes Involved in Drug Metabolism

• Cytochrome P450 enzymes (CYPs) are the most important enzymes in Phase I metabolism, responsible for oxidation, reduction, and hydrolysis reactions
  • Located primarily in the liver, but also found in the intestines, kidneys, lungs, and brain
  • Nomenclature: CYP followed by a number for the family, a letter for the subfamily, and another number for the specific enzyme (e.g., CYP3A4)
• CYP3A4 is the most abundant CYP in the liver and intestines, metabolizing over 50% of clinically used drugs
  • Examples: Statins, calcium channel blockers, benzodiazepines, immunosuppressants
• CYP2D6 is highly polymorphic, with over 100 known allelic variants, leading to wide interindividual variability in drug metabolism
  • Examples: Antidepressants, antipsychotics, opioids, beta-blockers
• CYP2C9 metabolizes many nonsteroidal anti-inflammatory drugs (NSAIDs) and oral anticoagulants
  • Examples: Warfarin, ibuprofen, diclofenac
• Uridine diphosphate-glucuronosyltransferases (UGTs) are the main enzymes involved in glucuronidation reactions
• Sulfotransferases (SULTs) catalyze sulfation reactions
• N-acetyltransferases (NATs) are responsible for acetylation reactions
• Glutathione S-transferases (GSTs) catalyze the conjugation of glutathione to drugs or reactive metabolites

Factors Affecting Drug Metabolism

• Age: Neonates and elderly individuals generally have reduced drug metabolism due to immature or declining liver function
• Genetic polymorphisms in drug-metabolizing enzymes can result in poor, intermediate, extensive, or ultrarapid metabolizers
  • Example: CYP2D6 polymorphisms can lead to increased risk of adverse effects or therapeutic failure
• Liver disease can impair drug metabolism by reducing the activity of CYPs and other enzymes
• Drug-drug interactions can occur when one drug induces or inhibits the metabolism of another drug
  • Induction increases the activity of drug-metabolizing enzymes, leading to faster clearance and reduced effectiveness of the affected drug
  • Inhibition decreases the activity of drug-metabolizing enzymes, leading to slower clearance and increased risk of adverse effects
• Diet and nutritional status can influence drug metabolism
  • Example: Grapefruit juice inhibits CYP3A4, increasing the bioavailability of many drugs
• Smoking induces CYP1A2, leading to faster metabolism of drugs like clozapine and olanzapine
• Alcohol consumption can induce CYP2E1, but chronic alcohol use can also impair liver function and drug metabolism

Toxicology Basics

• Toxicology studies the adverse effects of chemicals, including drugs, on living organisms
• Toxicity can be acute (short-term, high-dose exposure) or chronic (long-term, low-dose exposure)
• The dose-response relationship is a fundamental concept in toxicology, describing the relationship between the dose of a substance and the observed effect
  • The dose determines the poison: Even essential substances can be toxic at high doses
• Lethal dose 50 (LD50) is the dose that causes death in 50% of the exposed population, used to compare the toxicity of different substances
• Therapeutic index (TI) is the ratio of the lethal or toxic dose to the therapeutic dose, indicating the safety margin of a drug
  • A higher TI means a wider safety margin and lower risk of toxicity
• Reactive metabolites are chemically reactive compounds formed during drug metabolism that can bind to cellular macromolecules (proteins, DNA) and cause toxicity
  • Example: Acetaminophen (paracetamol) overdose leads to the formation of a reactive metabolite (NAPQI) that depletes glutathione and causes liver damage
• Idiosyncratic drug reactions are rare, unpredictable adverse reactions that are not dose-dependent and may have an immunological or genetic basis

Drug-Drug Interactions

• Pharmacokinetic interactions occur when one drug alters the absorption, distribution, metabolism, or excretion of another drug
  • Example: Rifampin, a potent CYP3A4 inducer, can decrease the effectiveness of oral contraceptives
• Pharmacodynamic interactions occur when drugs have additive, synergistic, or antagonistic effects on the same target or physiological process
  • Example: Combining opioids with benzodiazepines can lead to respiratory depression and increased risk of overdose
• Protein binding interactions can occur when drugs compete for binding sites on plasma proteins (albumin, alpha-1-acid glycoprotein)
  • The displaced drug may have increased free concentration and enhanced effects or toxicity
• Transporter interactions involve drugs that are substrates, inhibitors, or inducers of drug transporters (P-glycoprotein, organic anion transporting polypeptides)
  • Example: Cyclosporine, a P-glycoprotein inhibitor, can increase the bioavailability of digoxin
• Herb-drug interactions can occur between herbal supplements and prescription medications, often involving CYP enzymes or drug transporters
  • Example: St. John's wort, a CYP3A4 inducer, can reduce the effectiveness of many drugs

Clinical Implications and Case Studies

• Personalized medicine aims to tailor drug therapy based on an individual's genetic profile, particularly for drug-metabolizing enzymes and transporters
  • Example: Dosing of warfarin based on CYP2C9 and VKORC1 genotypes
• Therapeutic drug monitoring (TDM) involves measuring drug concentrations in the blood to optimize dosing and prevent toxicity
  • Commonly used for drugs with narrow therapeutic indices (lithium, digoxin) or high interindividual variability (tacrolimus, vancomycin)
• Adverse drug reactions (ADRs) are a major cause of morbidity and mortality, often related to drug metabolism and interactions
  • Example: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe skin reactions associated with certain drugs (allopurinol, carbamazepine)
• Drug metabolism and toxicology knowledge is crucial for drug development and safety assessment
  • In vitro and in vivo studies are conducted to characterize the metabolic profile and potential toxicity of new drug candidates
• Clinical case studies illustrate the importance of understanding drug metabolism and interactions in patient care
  • Example: A patient taking warfarin experiences bleeding after starting a course of antibiotics (erythromycin, a CYP3A4 inhibitor)
  • Example: A patient on a stable dose of phenytoin, a CYP2C9 substrate, develops toxicity after starting fluconazole, a CYP2C9 inhibitor