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Questions and Answers
Which CYP enzyme is known for metabolizing the highest number of drugs listed?
What is the primary purpose of conjugation reactions in drug metabolism?
Which of the following drugs is metabolized by CYP2C9?
Which CYP isoform is associated with the metabolism of clopidogrel?
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What role does content polarity play in the effectiveness of a drug under metabolic processing?
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What is the primary site for drug metabolism in the body?
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What characteristic do most drug metabolites have compared to the parent drug?
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Which of the following represents a prodrug?
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Which process enhances the water-solubility of drugs during metabolism?
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What type of reactions are primarily involved in drug metabolism in the liver?
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Which enzyme family is most associated with functionalisation reactions in drug metabolism?
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What is a common pathway of drug metabolism before excretion?
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Which of the following statements is true regarding the metabolism of paracetamol?
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Which cofactor is involved in the glucuronidation reaction?
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What is the primary reaction catalyzed by N-acetyltransferases?
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How can liver disease primarily impact drug metabolism?
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What interaction increases the risk of bleeding while using warfarin?
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Which substrate is involved in the sulfation reaction?
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Which of the following factors does NOT typically influence drug metabolism?
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Which drug is a substrate for glutathione-S-transferases?
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What is a common effect of drug interactions when two chemicals are present simultaneously?
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What is the primary organ responsible for the elimination of drugs from the body?
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What happens to the dosage of carbamazepine and phenytoin during pregnancy?
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What process refers to the irreversible loss of a drug from the site of measurement?
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Which of the following plays a significant role in drug uptake into hepatocytes?
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What is the term for the process where drugs are reabsorbed from the bile back into the liver?
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Which of the following statements about lipophilic drugs is true?
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Which enzymes are primarily responsible for the metabolism of drugs in the liver?
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What is the main organ responsible for drug excretion in the body?
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What is the primary purpose of maintaining drug concentration within a therapeutic range?
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What can the area under the plasma concentration versus time curve (AUC) indicate?
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Which of the following is NOT a key parameter in determining appropriate dosing regimens?
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What factor predominantly determines the hepatic clearance of a drug?
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Which statement describes low hepatic clearance drugs?
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What does plasma half-life relate to?
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Why is it important to consider individual patient characteristics when selecting drug dosing regimens?
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Which of the following is true about intravenous (IV) dosing?
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Study Notes
Drug Metabolism
- The process of chemically altering a drug, usually by enzymes.
- The liver is the primary site of metabolism but other organs, including the kidneys, lungs, and intestines, can be involved with certain drugs.
- Most drugs undergo some form of metabolism.
- Metabolic products often have less activity than the original drug (also known as the parent drug).
- Some metabolites can have more activity than the parent drug and are known as prodrugs.
- Prodrugs are activated in the liver to elicit a therapeutic response (e.g. codeine and clopidogrel).
- Metabolites are often more water-soluble, which can enhance their excretion.
- The vast majority of drugs are metabolized in the liver by functionalization and/or conjugation reactions.
Classification of Drug Metabolism Reactions
- A drug can be:
- Excreted as the unchanged parent drug (e.g. gentamicin).
- Undergo functionalization and be directly excreted (e.g. caffeine).
- Undergo conjugation and be directly excreted (e.g. paracetamol).
- Undergo functionalization followed by conjugation prior to excretion (e.g. phenytoin).
- These reactions can happen simultaneously, with a drug undergoing multiple pathways at once (e.g. codeine undergoing oxidation to morphine and glucuronidation to codeine-6-glucuronide).
Functionalization Reactions
- Introduce or unmask polar (charged) functional groups into the molecule to increase water solubility.
- Common functionalization reactions include:
- Dealkylation (de-ethylation or de-methylation).
- Hydrolysis.
- Hydroxylation.
- Oxidation.
- Metabolite activity can vary, leading to increased activity, a change in activity, or even toxicity (e.g. paracetamol).
- Cytochrome P450 (CYP) enzymes are a major family of enzymes responsible for many functionalization reactions.
- Other functionalization enzymes include:
- Esterases.
- Alcohol dehydrogenase.
- Xanthine oxidase.
Cytochrome P450 System
- Located on the smooth endoplasmic reticulum of cells, particularly abundant in hepatocytes.
- Involved in the metabolism of drugs, environmental pollutants, and dietary chemicals.
- Also involved in the synthesis of bile acids, hormones, and fatty acids.
- More than 50 individual CYP enzymes, classified based on their amino-acid sequence.
- Families 1, 2, and 3 are known to metabolize drugs.
- CYP3A4 is a key enzyme, being the fourth member of CYP family 3 sub-family A.
Main CYPs Involved in Human Hepatic Drug Metabolism
- CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4
Drugs Metabolized by Specific CYP Enzymes
- CYP1A2: Amitriptyline, caffeine, clozapine, haloperidol, lidocaine (lignocaine), olanzapine, ondansetron, tamoxifen
- CYP2C8: Chloroquine, montelukast, paclitaxel
- CYP2C9: Celecoxib, diclofenac, gliclazide, ibuprofen, irbesartan, losartan, naproxen, phenytoin, sildenafil, sulfonylurea, S-warfarin
- CYP2C19: Citalopram, clopidogrel, diazepam, esomeprazole, omeprazole, pantoprazole, sertraline
- CYP2D6: Amitriptyline, codeine, dexamfetamine, dextromethorphan, fluoxetine, fluvoxamine, haloperidol, metoprolol, mirtazapine, perhexiline, quetiapine, risperidone, timolol, venlafaxine
- CYP2E1: Ethanol, halothane, methoxyflurane
- CYP3A4: Amiodarone, aprepitant, atorvastatin, carbamazepine, ciclosporin, erythromycin, felodipine, hydrocortisone, HIV protease inhibitors (e.g. saquinavir), simvastatin, tacrolimus, tyrosine kinase inhibitors (e.g. axitinib), verapamil, zolpidem
Conjugation Reactions
- Involve joining a suitable functional group present in the drug molecule with a polar group of an endogenous substance in the body (e.g. glucuronic acid, sulfate, acetyl-coenzyme A or glutathione).
- The conjugated drug molecule is generally more polar or water-soluble, which enhances urinary excretion.
Table of Conjugation Reactions
| Enzyme | Cofactor | Reaction | Substrate / Metabolite |
|---|---|---|---|
| UDP-glucuronosyltransferases | UDP-glucuronic acid | Glucuronidation | Morphine/morphine-3-glucuronide, Codeine/codeine-6-glucuronide |
| Sulfotransferases | Sulfate | Sulfation | Salbutamol/salbutamol sulfate, Paracetamol/paracetamol sulfate |
| N-acetyltransferases | Acetyl-CoA | Acetylation | Isoniazid/acetylisoniazid, Clonazepam/7-acetamido-clonazepam |
| Glutathione-S-transferases | Glutathione | Glutathione conjugation | Paracetamol/paracetamol–glutathione conjugate |
Variability in Drug Metabolism
- Genetics: Individual differences in enzyme activity can lead to variability in drug metabolism.
- Environmental Factors: Co-administered drugs (drug-drug interactions), diet, alcohol, smoking can impact metabolism.
- Age and Gender: Metabolism can vary significantly with age, particularly in infants and elderly.
- Disease States: Diseases like liver, cardiovascular diseases can alter drug metabolism.
- Hormonal Changes: Pregnancy, particularly the third trimester, can increase or decrease metabolism.
Drug Interactions
- Metabolic drug interactions occur when two or more chemicals (drugs or environmental chemicals) are present in the body simultaneously.
- One chemical can alter the activity of the enzyme involved in eliminating the other chemical (drug-drug, drug-herb, or even drug-food interactions).
- Enzyme inhibition or induction (faster metabolism) are the primary mechanisms of drug-drug interactions.
Examples of Significant Drug Interactions (Inhibition-Type Metabolism)
- Inhibition of warfarin metabolism by amiodarone or fluconazole, increasing the risk of bleeding.
- Inhibition of azathioprine metabolism by allopurinol, increasing the risk of severe bone marrow toxicity and death.
- Inhibition of ciclosporin and tacrolimus metabolism by erythromycin, increasing the risk of nephrotoxicity and neurotoxicity.
- Inhibition of diazepam metabolism by cimetidine, prolonging central nervous system depression.
Disease States
- Liver disease: The effects are difficult to predict, as they depend on disease type and severity.
- In severe cirrhosis and viral hepatitis, the clearance of drugs metabolized by CYP is decreased.
- Cardiac failure: Decreases liver perfusion and oxygenation, which can reduce the activity of drug-metabolizing enzymes.
Hormonal Factors
- Pregnancy: Can increase the activity of CYP and UGT enzymes, particularly during the third trimester.
- Metabolism of caffeine may decline during pregnancy.
- Carbamazepine and phenytoin doses may need to be increased to maintain therapeutic plasma levels.
Excretion of Drugs and Metabolites
- Elimination: Refers to the irreversible loss of drug from the site of measurement by metabolism and excretion, but metabolites may remain.
- Excretion: Applies solely to the loss of unchanged drug or metabolites.
- The liver is the primary organ of elimination.
- The kidneys are the primary organ of excretion.
Hepatic and Biliary Excretion
- Lipophilic drugs diffuse freely across hepatocyte membranes.
- Transporters like OATP, OCT, OAT facilitate the uptake of drugs that are cations, anions, and other polar compounds.
- Drug metabolism occurs within the hepatocyte by CYP and UGT enzymes, or drugs can be excreted into the bile by efflux transporters like P-gp and BCRP.
- Hepatocyte-formed metabolites can:
- Diffuse back into the blood for subsequent urinary excretion.
- Be transported into the bile for fecal excretion.
Enterohepatic Recycling
- Drugs and metabolites excreted into bile can be reabsorbed in the small intestine.
- This reabsorbed drug can then return to the liver via the portal vein, a process known as enterohepatic recycling.
- Many drugs (e.g. atorvastatin, digoxin, etc.) undergo enterohepatic cycling to some degree.
PK Parameters and Dosing Regimens
- The rationale for drug use assumes that a specific drug concentration will have the desired therapeutic effect with minimal adverse effects.
- Many drugs have a relationship between plasma drug concentration and clinical response, allowing for therapeutic range maintenance.
- Therapeutic ranges are often based on population-level data rather than individual patient characteristics.
- For some drugs, dosing must be tailored to individual factors (age, health status, kidney and liver function, drug PK properties).
Single Oral Dose Plasma Concentration – Time Profile
- Onset of action: ~2 hours.
- Peak plasma concentration: At 5 hours.
- Duration of action: 6 hours.
- IV dosing: Not influenced by absorption.
Key Pharmacokinetic Parameters
- Clearance: The ability of an organ or the body to eliminate a drug. Clearance by each organ is additive. CLSystemic=CLRenal+CLHepatic+CLOther
- Volume of Distribution: Reflects the extent of drug distribution in the body.
- Half-life: Time taken for the plasma concentration of a drug to reduce by 50%. Half-life is directly related to volume of distribution and inversely related to drug clearance.
- Area Under the Plasma Concentration Versus Time Curve (AUC): Describes drug concentration in the systemic circulation as a function of time. It plays a role in the calculation of drug clearance after IV administration and its bioavailability (comparing AUC of IV and oral administration of the same drug).
Hepatic Clearance
- CLH = Hepatic extraction ratio (EH) multiplied by liver blood flow (QH).
- CLH = EH X QH
- Low hepatic clearance drugs are considered capacity-limited: Liver enzyme capacity is the rate-limiting factor for extraction.
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Description
Explore the fascinating process of drug metabolism, focusing on the chemical alterations of drugs primarily in the liver. Learn about the roles of enzymes, metabolites, and prodrugs, as well as the various reactions involved in drug metabolism. This quiz will enhance your understanding of how drugs are processed in the body.
