Metabolism

Metabolism Definition

• The process where a xenobiotic or endobiotic is enzymatically transformed into a more polar, water-soluble, excretable form.

Metabolism Sites

• Hepatic microsomal enzymes: Responsible for oxidation and conjugation.
• Extrahepatic microsomal enzymes: Also responsible for oxidation and conjugation.
• Hepatic non-microsomal enzymes: Responsible for acetylation, sulfation, glutathione conjugation, alcohol/aldehyde dehydrogenase, hydrolysis, and oxidation/reduction.
• Extrahepatic locations: Intestine, brain, lungs, skin, heart, kidneys, GIT, and blood.

Fate of a Drug

• An active drug can be metabolized into an inactive, active, or toxic metabolite.
• Prodrugs that are not yet active can be metabolized into an active form.

Activity and Toxicity Implications

• Active metabolites: Can have the same, better, altered, or less activity than the original drug.
• Inactive metabolites: Drugs are pharmacologically inactive.
• Toxic metabolites: Can be toxic.

Advantages and Disadvantages of Metabolism

• Advantages:*
• Prevents prolonged effects of drugs in the body.
• Detoxifies drugs.
• Allows for prodrug strategies.
• Disadvantages:*
• Can produce side effects and toxic effects.
• Can lead to loss of drug activity.
• Can alter therapeutic effects.

Clinical Significance of Metabolism

• Impacts drug therapy for metabolic, genetic, and environmentally-related illnesses.
• Can cause problems with long-term therapy due to toxicity and/or active metabolites.
• Contributes to drug-drug or drug-food interactions.
• Aids in assessing drug efficacy, safety, and designing dosage regimens.
• Provides insight into toxic processes like carcinogenesis and tissue necrosis.
• Helps understanding enzymes involved in drug metabolism, which are important for metabolizing endogenous substances.

Enzymes Involved in Metabolism

• Cytochrome P450s (Cyps): The most important and major enzymes involved in metabolism.
  • CYP3A4, CYP2E1, CYP2D6, CYP2C9, and CYP2C19 account for 75% of drug metabolism.
• Other enzymes:
  • UDP-glucuronosyl transferases (UGTs)
  • Glutathione-S-transferases (GSTs)
  • Sulfotransferases (STs)
  • N-acetyl transferases (NATs)
  • Catechol-O-methyltransferase (COMT)

Types of Metabolism

• First-pass metabolism: When a drug is metabolized in the liver before it reaches the general circulation (mostly by CYP3A4).
  • Highly lipophilic drugs are more susceptible to this.
  • Can impact the bioavailability of drugs.
  • Alternating routes of administration can be used (IV, topical, rectal).
• Phase I Metabolism: Includes reactions like oxidation, reduction, and hydrolysis.
• Phase II Metabolism: Includes conjugation reactions with various molecules, including glucuronidation, sulfation, amino acid conjugation, glutathione conjugation, acetylation, and methylation.

Factors Affecting Metabolism

• Internal Factors:*
• Genetics: Enzyme variability impacting metabolism (e.g., poor metabolizers, intermediate metabolizers, extensive metabolizers, ultrarapid metabolizers).
• Ethnicity: Can influence enzyme activity.
• Age: Enzyme activity changes with age.
• Gender: Some metabolic enzymes have sex-based differences.
• Disease States: Liver and kidney disease can significantly impact metabolism, as can diseases like heart failure or chronic obstructive pulmonary disease.
• External Factors:*
• Drugs: Can be enzyme inducers or inhibitors.
• Diet: Some foods may influence metabolism.
• Environment: Exposure to chemicals or toxins can impact metabolic processes.

Clinical Significance of Metabolism: Cases

• Enzyme Inducers: Drugs or other factors that increase enzyme activity (can lead to lower levels of other drugs being metabolized and require dose adjustments).
• Enzyme Inhibitors: Drugs or other factors that decrease enzyme activity (can lead to higher levels of other drugs being metabolized and require dose adjustments).
• Liver Diseases: Can reduce enzyme activity and affect drug metabolism.
• Kidney Diseases: Can reduce drug excretion and lead to drug accumulation.

First Pass Metabolism Exercise

• First Pass metabolism can be avoided by transdermal patches (I) and buccal (II) formulations. (Correct answer: D.)
• Propranolol given IV will still undergo first pass metabolism in the liver, but its bioavailability will not be significantly reduced because it has already entered circulation. (Correct answer: B.)

Phase I & Phase II Metabolism Exercise

• Oxidation, reduction, hydrolysis are Phase I reactions. Sulfation is a Phase II reaction. (Correct answer: B.)
• The example shows a hydroxylation reaction, which is a Phase I metabolic reaction. (Correct answer: Phase I)

Water Solubility and Phase II Reactions

• Methylation is the only reaction that would decrease water solubility (not glucuronidation, hydroxylation, N-dealkylation, or hydrolysis). (Correct answer: E.)

Clinical Significance of Metabolism: Exercise

• Mr. X should NOT be given Losartan because Ketoconazole is a strong CYP3A4 inhibitor, which will lead to increased Losartan levels (likely causing toxicity). (Correct answer: B.)
• Mr. X should NOT continue Losartan because he has severe liver dysfunction, which impairs drug metabolism. (Correct answer: B.)