3.4 Biotransformation and drug metabolism

Biotransformation and drug metabolism are crucial processes in pharmacokinetics. They involve the body's mechanisms for altering and eliminating drugs, affecting how medications work and how long they stay active. Understanding these processes is key to grasping drug efficacy, toxicity, and individual responses.

This topic dives into the organs involved in drug metabolism, focusing on the liver's role. It also explores cytochrome P450 enzymes and genetic variations that impact drug metabolism. These factors significantly influence how drugs behave in different people, shaping personalized medicine approaches.

Drug metabolism: Purpose and process

Biochemical modification and elimination of drugs

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• Drug metabolism biochemically modifies pharmaceutical substances in living organisms to facilitate elimination from the body
• Process typically involves two phases
  • Phase I reactions (functionalization) introduce or expose functional groups on drug molecules through oxidation, reduction, or hydrolysis
  • Phase II reactions conjugate drugs or metabolites with endogenous substances (glucuronic acid, sulfate, amino acids)
• Increases water solubility of drugs making them more easily excreted through urine or bile
• Can form active metabolites potentially contributing to or altering pharmacological effects of parent drug

Impact on drug efficacy and toxicity

• Rate and extent of drug metabolism significantly impacts:
  • Drug efficacy
  • Toxicity
  • Duration of action in the body
• Affects bioavailability of orally administered drugs through first-pass metabolism in gastrointestinal tract
• Influences optimal dosing and dosing frequency
• Can lead to drug-drug interactions when metabolism of one drug affects another
• May cause variations in drug response between individuals due to genetic differences in metabolic enzymes

Organs involved in drug metabolism

Primary metabolic organs

• Liver contains highest concentration of drug-metabolizing enzymes serving as primary site of drug metabolism
  • Houses major cytochrome P450 enzymes
  • Performs bulk of Phase I and II reactions
• Gastrointestinal tract plays crucial role in first-pass metabolism
  • Contains CYP3A4 enzymes in intestinal epithelium
  • Affects bioavailability of orally administered drugs
• Kidneys contribute through various enzymatic reactions
  • Metabolize certain drugs and their metabolites
  • Important for drugs primarily excreted in urine

Secondary metabolic organs

• Lungs contain enzymes capable of metabolizing some inhaled drugs and environmental toxins
  • Important for metabolism of inhaled anesthetics
  • Involved in biotransformation of some airborne pollutants
• Skin possesses metabolic enzymes affecting topically applied drugs and environmental compounds
  • Contributes to metabolism of transdermal medications
  • Provides barrier against environmental toxins
• Brain has limited drug-metabolizing capacity but can metabolize certain neuroactive compounds
  • Important for metabolism of some psychoactive drugs
  • Affects local concentrations of centrally-acting medications
• Other organs (heart, skeletal muscle, blood) contribute to lesser extent
  • May be important for specific drugs or in certain conditions

Cytochrome P450 enzymes in drug metabolism

Structure and function of CYP450 enzymes

• Cytochrome P450 (CYP450) enzymes form superfamily of heme-containing proteins
• Play central role in Phase I drug metabolism
• Catalyze various oxidative reactions:
  • Hydroxylation (adding -OH group)
  • Dealkylation (removing alkyl group)
  • Epoxidation (forming epoxide ring)
• Exhibit broad substrate specificity allowing metabolism of structurally diverse compounds
• Major isoforms involved in drug metabolism:
  • CYP3A4 (most abundant, metabolizes ~50% of clinically used drugs)
  • CYP2D6
  • CYP2C9
  • CYP2C19
  • CYP1A2

Regulation and variability of CYP450 activity

• Activity can be induced or inhibited by various factors:
  • Other drugs (leading to drug-drug interactions)
  • Environmental compounds
  • Dietary components (grapefruit juice inhibits CYP3A4)
• Genetic polymorphisms in CYP450 genes result in inter-individual variations:
  • Affect drug metabolism rates
  • Influence therapeutic responses
  • Can lead to adverse drug reactions
• Expression levels can vary between individuals and populations
• Some isoforms show tissue-specific expression patterns

Genetic variations vs drug metabolism

Types of genetic variations affecting drug metabolism

• Single nucleotide polymorphisms (SNPs) in CYP450 genes common source of variation
  • Can alter enzyme activity or expression levels
  • Examples: CYP2D64, CYP2C192
• Copy number variations (CNVs) affect number of functional gene copies
  • Can lead to increased or decreased enzyme activity
  • Example: CYP2D6 gene duplication
• Genetic variations in other drug-metabolizing enzymes:
  • Phase II enzymes (UGTs, GSTs)
  • Drug transporters (ABCB1, SLCO1B1)

Impact of genetic variations on drug therapy

• Individuals classified based on genetic makeup:
  • Poor metabolizers (reduced enzyme activity)
  • Intermediate metabolizers
  • Extensive metabolizers (normal enzyme activity)
  • Ultrarapid metabolizers (increased enzyme activity)
• Genetic variations can result in:
  • Altered drug efficacy
  • Increased risk of adverse reactions
  • Changes in optimal dosing requirements
• Pharmacogenetic testing identifies genetic variations to guide personalized therapy
  • Helps predict drug response
  • Allows for dose adjustments
  • Example: Warfarin dosing based on CYP2C9 and VKORC1 genotypes
• Ethnic differences in prevalence of genetic polymorphisms contribute to population-specific variations
  • Example: Higher frequency of CYP2D6 poor metabolizers in Caucasians compared to Asians
• Understanding genetic variations crucial for implementing precision medicine approaches