Quartz 5

Pharmacokinetics of Metabolism

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Pharmacokinetics

Metabolism: Transformation / Alteration of the drug

  1. Facilitates elimination by making the drug more hydrophilic
  2. Can convert (Biotransformation) certain active substance into:
    1. More active metabolites: Albendazole
      1. Including activation of inactive prodrugs into active metabolites (Ex: ACE Inhibitors)
    2. Less active metabolites
    3. Inactive metabolites: No effect
    4. Toxic metabolites:
      1. Paracetamol: Synthesis of hepatotoxic NAPQI when the Sulphate conjugation and Glucuronidation pathways are saturated
      2. Ionophores Antibiotics
    5. Metabolites with different pharmacologic action

Unhepatic patients = Patients with a non-functioning liver, the drug metabolism is severely impaired. Another organ becomes the next major site of metabolism

Phases of Metabolism:

  1. Phase I: Oxidation / Reduction reactions to make the compound more polar > more hydrophilic > facilitates kidney excretion
    1. Works by adding or unmasking polar functional groups: -OH, -SH, -NH2, -COOH …
    2. May be sufficient for excretion
    3. Reactions types:
      1. Oxidation: Alkylation (Including Methylation), Dealkylation (Including Demethylation), Ring cyclization, N-carboxulation, Dimerization, Transamidation, Isomerization, Decarboxylation, Hydrolytic cleavage
      2. Reduction (More rare)
      3. Hydrolytic cleavage
    4. Reactions catalyzed by enzymes:
      1. Monooxygenases = Mixed function oxidases
        1. Cytochrome P450 CYP450 enzymes
        2. NADPH Cytochrome C reductase (Flavoprotein)
      2. Epoxide hydrolases
      3. Esterases
      4. Alcohol dehydrogenases
      5. Aldehyde dehydrogenases
      6. Flavin-containing monooxygenases
      7. Xanthine oxidases
      8. Amine Oxidases (MAOs)
  2. Phase II: Conjugation with endogenous compounds to make the compound even more hydrophilic
    1. Conjugation reactions:
      1. Glucuronidation: By UDP-Glucuronosyltransferase
      2. Sulfation: By Sulfotransferase
      3. Acetylation: By Acetyltransferase
      4. Amino Acid conjugation
      5. Glutathione conjugation: By Glutathione-S-transferase
      6. Fatty Acid conjugation
      7. Condensation reactions
    2. Rarely, drugs can be metabolized directly from Phase II reaction (Skip Phase I)
  3. Then Excretion of the hydrophilic metabolite

CYP450 family enzymes:

  1. Catalysts of phase I metabolism
  2. Wide substrate spectrum: Can metabolize many different molecules
  3. Highest abundance
  4. Most active in the liver: The liver is the main site of drugs metabolism
    1. Also present in a lesser extent in the GI, Kidney, Lungs…
  5. Located IC on the membrane of the Smooth Endoplasmic Reticulum SER
  6. Nomenclature: CYPxyz
    1. CYP: Superfamily of enzymes
    2. x: Family (≥40% of sequence homology)
    3. y: Subfamily (≥55% of sequence homology)
    4. z: Isoform
  7. CYP1, CYP2, CYP3 Families enzymes are used for metabolism of xenobiotics = Metabolism of foreign molecules
    1. Their activity can be modulated (Induced or Inhibited) by certain drugs and cause drug-drug interaction
    2. CYP1 :
      1. Metabolizes: Caffeine, Theophylline, Paracetamol, Thiabendazole
      2. Induced by: Omeprazol, Dioxin, Indole-3-Carabinole
      3. Inhibited by: Ciprofloxacin, Fluvoxamine, Cimetidine, Aciclovir
    3. CYP2:
      1. Metabolizes: Phenytoin, Warfarin, Omeprazol, β-BLockers (Sympatholytics), Halothane, Paracetamol
      2. Induced by: Phenobarbital, Rifampicin, Isoniazide, Ethanol
      3. Inhibited by: Terbinafine, Fluconazole
    4. CYP3:
      1. Metabolizes: Benzodiazepines (BDZ), Clarithromycin, Erythromycin, Codeine, Fentanyl, Steroid Hormones
      2. Induced by: Phenobarbital, Phenytoin, Carbamazepine, Rifampicin, Dexamethasone
      3. Inhibited by: Pleuromutilins, Macrolides, Azoles (Ex: Ketoconazole)
      4. In mammals, CYP3A has the highest importance

Drug-drug interactions can occur on a Metabolic level:

  1. CYP450 Inhibiting drugs reduce the liver metabolism of other drugs > Increased efficacy
    1. Pleuromutilins, Macrolides, Sulfonamides, Ketoconazole are CYP450 inhibitors
      1. Ketoconazole can be used to increase the bioavailability of Cyclosporine which is expensive
    2. Mixing them with Ionophores Antibiotics can be lethal
  2. CYP450 Inducing drugs increase the liver metabolism of other drugs > Decreased efficacy
    1. Phenobarbital is a CYP450 inducer
  3. Metabolic pathway saturation: Shifts the metabolism to alternate pathways
    1. Paracetamol’s main metabolic pathways are the Sulphate conjugation and Glucuronidation, the alternative pathway (Through CYP450) produces toxic NAPQI metabolites
      1. If the main pathways are already saturated by other drugs, the proportion of produced NAPQI will be greater

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