Hepatic Microsomal Enzymes and Drug Metabolism

• Drug interactions involve hepatic microsomal enzymes.

Introduction

• The liver is the largest internal organ in the body.
• It plays a central role in metabolism, detoxification, and the synthesis of essential proteins.
• It regulates chemical levels in the blood and processes drugs and toxins to make them easier for the body to excrete
• One of its critical functions is drug metabolism, primarily involving hepatic microsomal enzymes.

Biotransformation

• It describes the process by which the body chemically modifies drugs to facilitate their elimination.
• It primarily occurs in the liver.
• The primary goal of metabolism is to make drugs more water-soluble so, they can be excreted via urine or bile.

Phases of Drug Metabolism

• Phase I Modification: oxidation, reduction, hydrolysis.
• Phase II Conjugation: glucuronidation, sulfation.
• Excretion: kidney, bile.

Phase I (Functionalization Reactions)

• Oxidation is performed by CYP450 enzymes.
• Reduction is performed by nitroreductases and azoreductases.
• Hydrolysis is performed by esterases and amidases.

Phase II (Conjugation Reactions)

• Glucuronidation is performed with UDP-glucuronosyltransferases (UGTs).
• Acetylation performed with N-acetyltransferases (NATs).
• Sulfation is performed with sulfotransferases (SULTs).
• Glutathione conjugation is performed with glutathione-S-transferases (GSTs).

Hepatic Microsomal Enzymes

• A group of enzymes that are responsible for drug metabolism.
• They are mainly found in the smooth endoplasmic reticulum of liver cells.
• They play a key role in Phase I metabolism, helping in oxidation, reduction, and hydrolysis of drugs.
• The Cytochrome P450 (CYP450) system metabolizes over 75% of drugs.

Major Microsomal Enzymes & Their Functions

• Cytochrome P450 (CYP450) metabolizes most drugs.
• Flavin-Containing Monooxygenases (FMO) break down drugs that contain nitrogen, sulfur, or phosphorus, like nicotine and ranitidine.
• Microsomal Epoxide Hydrolase (mEH) converts epoxides into active metabolites, such as carbamazepine.
• UDP-Glucuronosyltransferases (UGTs) help in drug detoxification through glucuronidation, such as acetaminophen.

Factors Affecting Hepatic Microsomal Enzymes (CYP450)

• Physiological factors such as age, sex, and nutrition influence enzyme function.
• Aging reduces activity, while diet (fasting or high-fat) affects CYP3A4 metabolism.
• CYP gene variations affect drug metabolism speed, making some individuals metabolize drugs faster or slower.
• Liver diseases like cirrhosis, hepatitis, NAFLD lower CYP activity, slowing drug metabolism and increasing drug buildup.
• Alcohol, smoking, pollutants, and certain drugs can increase or decrease CYP enzyme activity, altering drug breakdown.

Diseases Affecting Hepatic Microsomal Enzymes

• Liver diseases (cirrhosis, hepatitis) reduce enzyme activity, slowing drug metabolism.
• Acute liver injury (acetaminophen toxicity) disrupts enzyme function.
• Genetic disorders such as CYP450 mutations alter drug metabolism.
• Endocrine disorders like thyroid imbalances affect enzyme activity.
• Infections such as HIV and TB impact liver enzyme function.
• Alcoholism and cancer modify enzyme activity, affecting drug breakdown.

Hepatic Microsomal Enzyme Inducers

• Substances that increase liver enzyme activity (mainly CYP450), speeding up drug metabolism and reducing drug effectiveness.
• Common inducers include phenytoin, carbamazepine, phenobarbital, rifampicin, and chronic alcohol consumption.
• Rifampicin and Warfarin are a strong inducer combination that lowers anticoagulant effects and increases risk of clots.
• Carbamazepine and Oral Contraceptives are a moderate to strong inducer combination that reduces effectiveness and increases risk of pregnancy.
• Phenytoin and Theophylline are a weaker inducer combination and reduces asthma drug effectiveness.

Hepatic Microsomal Enzyme Inhibitors

• Inhibitors are substances that inhibit liver enzymes (mainly CYP450), slowing down drug metabolism.
• They block enzyme activity to prevent drug breakdown.
• They increase drug levels which can prolong drug effects and increase toxicity risk.
• Common inhibitors include ketoconazole, erythromycin, and cimetidine.
• Ketoconazole and Warfarin are a strong inhibitor combination and can result in higher warfarin levels and increased bleeding risk.
• Cimetidine and Warfarin are a moderate to strong inhibitor combination and can result in reduced theophylline clearance and risk of toxicity.
• Erythromycin and Theophylline are a weaker inhibitor combination and can result in slower warfarin metabolism and increased anticoagulant effect.

Effect of Drugs on Hepatic Microsomal Enzymes

• Hepatic microsomal enzymes (CYP450) play a key role in drug metabolism.
• Some drugs can induce enzymes to speed up metabolism, lower drug levels.
• Some drugs can inhibit enzymes to slow metabolism and increase drug levels.
• Affects drug levels, which requires monitoring.
• Changes drug effectiveness and toxicity risk, which requires adjusted doses.
• Monitoring is essential for safe & effective drug use.

Examples Hepatic Microsomal Enzyme Inducers

• Rifampin induces CYP3A4, CYP2C9, CYP2C19 CYP2C8, used in tuberculosis and is a strong inducer that affects many drugs.
• Phenobarbital induces CYP2B6, CYP3A4, and CYP2C9 and is considered a classic inducer in epilepsy treatment.
• Phenytoin induces CYP3A4, CYP2C9, and CYP2C19, induces metabolism of anticoagulants and steroids.
• Omeprazole induces CYP1A2, and affects caffeine and theophylline metabolism.

Examples Hepatic Microsomal Enzyme Inhibitors

• Phenelzine inhibits CYP2C8 and MAO inhibitors that block the enzyme to increase drug levels and side effect risk.
• Montelukast inhibits CYP2C8 and leukotriene receptor antagonists rely on CYP2C8, inhibitors may lower metabolism and efficacy.
• Thiotepa inhibits CYP2B6, and chemotherapeutics need CYP2B6, inhibitors may reduce effectiveness.
• Clopidogrel inhibits CYP2B6, antiplatelet drugs rely on CYP2B6 for activation, inhibition reduces their effectiveness, which requires careful monitoring.