3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.1. Pharmacology principles
                      3.1.3.1.1. Pharmacokinetics
 3.1.3.1.1.5. Drug metabolism 

Drug metabolism

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=== Unfinished ===

Need to add stuffs about slow/fast acetylators

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Role of metabolism

  • .. to convert lipid-soluble drug into water-soluble metabolites
  • By increasing water solubility
    --> Decrease Vd, and enhance renal excretion and sometimes GIT elimination
  • Metabolism does not always lead to pharmacologically inactive metabolite
    * e.g. diazepam and propranolol may be metabolised into active compounds

Rate of metabolism

Rate of metabolism depends on

  • Concentration of drug at the site of metabolism
  • Intrinsic rate of metabolism process

First-order kinetics

  • Amount of drug eliminated is proportional to the plasma concentration
    * e.g. Most drugs

Zero-order kinetics

  • Constant amount of drug is eliminated, regardless of plasma concentration
    * Occurs when the plasma concentration exceeds enzyme capacity
    * e.g. alcohol, aspirin, phenytoin

Pathways of metabolism

4 basic pathways

  1. Oxidation
    * e.g. hydroxylation, deamination, desulfuration, dealkylation, dehalogenation
    * Reactive intermediates may cause organ damage
  2. Reduction
    * More common when oxygen partial pressure is low
  3. Hydrolysis
    * Do not involve cytochrome P-450 enzymes
    * Nonmicrosomal enzymes are involved
  4. Conjugation
    * Conjugation with glucuronic acid involves cytochrome P-450 enzymes
    * Decreased in neonates and during pregnancy

2 phases

  1. Phase I
    * Oxidation, reduction, and hydrolysis
    * Increase drug's polarity, preparing it for phase II
  2. Phase II
    * Conjugation reactions
    * Increase water solubility by linking with a highly polar molecule

Site of metabolism

  • Liver
  • Plasma (Hofmann elimination, ester hydrolysis)
  • Lungs
  • Kidneys
  • GIT
    * Especially small intestine
    * Cytochrome P-450 enzymes

Enzymes involved

  • Microsomal enzymes
    * Mainly located in the hepatic smooth endoplasmic reticulum
    * Can also be present in kidney, GIT, adrenal cortex

Phase I enzymes

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Enzymes involved in phase I reactions include:

  1. Cytochrome P-450 enzymes
  2. Non-cytochrome P-450 Enzymes (Esters)
  3. Flavin-containing monooxygenase enzymes

1. Cytochrome P-450 enzymes

aka mixed function oxidase system, or mono-oxygenases

  • Superfamily of membrane-bound heme proteins
    * Predominantly hepatic microsomal enzymes
    * Some mitochondrial P-450 enzymes
  • When combined with carbon monoxide
    --> peak absorption at 450nm
  • Involved in both oxidation and reduction
  • Functions as the terminal oxidase in the electron transport scheme

Grouping of cytochrome P-450 enzymes

  • Enzymes that share more than 40% of sequence homology
    --> Grouped into a family
    * e.g. CYP2
  • Enzymes that share more than 55% of sequence homology
    --> Grouped into a subfamily
    * e.g. CYP2A
  • Individual enzymes are then assigned an individual number
    * e.g. CYP2A6

Actions of cytochrome P-450 enzymes

  • 10 isoforms of cytochrome P-450 are responsible for the oxidative metabolism of most drugs
  • Most CYP activities are generated by CYP2D6, CYP3A4, CYP3A5
CYP3A4
  • Most abundant
  • Comprising 20% to 60% of total P-450 activity
  • CYP3A4 + CYP3A5
    --> Responsible for metabolism of more than half of the currently available drugs
    * e.g. opoids (alfentanil, sufentanil, fentanyl)
    * e.g. benzodiazepines, local anaesthetics (lidocaine, ropivacaine)
    * e.g. immunosuppresants (cyclosporine), antihistamines (terfenadine)
  • Gender dependent
    --> Clearance of some drugs are 20-40% higher in women
    * Due to stimulation by steroid hormone
CYP2D6
  • Responsible for 25% of drugs
  • e.g. analgesics, antidysrhythmics, amide local anesthetics, ketamine, propofol, antiemetics, and betablocker

 

For example,

  • Codeine is converted to morphine and morphine-6-glucuronide
    * By CYP2D6-mediated O-demethylation
  • Quinidine inhibits CYP2D6
    --> Markedly diminishes effect of codeine

 

Cytochrome P-450 and neonates

  • Hepatic microsomal enzyme activity is low in neonates
    * especially premature infants
    --> Interferes with conjugation
    --> Hyperbilirubinaemia of the neonate and risk of bilirubin encephalopathy

Cytochrome P-450 and enzyme induction

  • Hepatic microsomal enzyme activity can be stimulated by drugs/chemicals
  • Also occurs (to limited extent) in lungs, kidney, and GIT

 

For example,

  • Phenobarbital
  • Polycyclic hydrocarbons (e.g. in cigarette smoke)

NB:

  • May increase risk of halothane hepatotoxicity

2. Noncytochrome P-450 enzymes (esters)

aka nonmicrosomal enzymes

  • Involved in conjugation, hydrolysis
    * All conjugation reactions (except for conjugation of glucuronic acid)
  • Also involved (to less extent) in oxidation and reduction
  • Present mainly in liver, also plasma and GIT
  • (Plasma cholinesterase and acetylating enzymes) Do NOT undergo enzyme induction
    * Activity level determined genetically

 

For example,

  • Hydrolysis of drugs containing ester bonds
    * Includes succinylcholine, atracurium, mivacurium, esmolol, ester local anaesthetics

Atypical cholinesterase

  • Genetic mutation
  • Glycine is substituted for an aspartate in anionic binding site
    --> Loss of electrostatic interaction
    --> Less drug-substrate binding
    --> Dramatically increased duration of action for drugs such as succinylcholine and mivacurium

3. Falvin-containing monooxygenase enzymes

  • Nicotinamide-adenine dinucleotide (NAD)-dependent microsomal enzymes
  • Oxidise nitrogen, sulfur, and phosphorus-containing compounds

 

For example,

  • FMO3 catalyzes oxidation of tricyclic antidepressants and H2 antagonists

Phase II enzymes

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Enzymes involved in phase II reactions include:

  1. Glucuronosyltransferase
  2. Glutathione-S-transferase
  3. N-acetyl-transferase
  4. Sulfotransferase

Glucuronosyltransferase

Uridine diphosphate glucuronosyltransferase

  • A family of hepatic microsomal enzymes
  • Catalyses covalent addition of glucuronic acid to compounds
    --> More water soluble

 

Intestine contains beta-glucuronidase
--> Hydrolyse glucuronides back to parent compound
--> Reabsorbed and transport to liver for reconjugation
* Enterohepatic recirculation

 

For example,

  • Propofol
    --> Glucuronidation in liver and kidney
  • Opioids
    --> Undergoes glucuronidation
    * Morphine-3-glucuronide and morphine-6-glucuronide
  • Midazolam
    --> Glucuronidation product 1-hydroxymidazolam (active)
    * Contribute to prolonged effect in renal insufficiency

Glutathione-S-transferase

  • Primarily a defensive system for detoxification and oxidative stress
  • GST-dependent activation is responsible for compound A nephrotoxicity in rats
    * Absence of toxicity in human is probably a species difference

N-Acetyl-Transferase

  • Catalyse N-acetylation
  • Common phase II reaction for heterocyclic aromatic amines and arylamine hydrazine
  • Responsible for inactivation of isoniazid and hydralazine
  • Genetic polymorphism
    --> Fast and slow acetylators