11-Drug Metabolism

Question 1

Phase 1 Reactions

Answer 1

• First Pass, in the LIVER
• “Detoxification” –> lipophilic to more readily excreted polar products
• Reduction, Drug is modified to be more POLAR
• Oxidation, Polar groups are introduced
  
  • ​Hydroxylation
  • DeAMINation
  • DeALKYLation
  • SULFOXidation
• Hydrolysis, Polar groups are EXPOSED

Question 2

Phase 2 Reactions

Answer 2

• Occurs @ Liver, after Phase 1
• Drugs are broken down to Polar Metabolites
  
  • ​To dissolve in plasma and excreted by kidneys
• CONJUGATION
  
  • Glucoronic Acid
  • Sulfuric Acid
  • Glutathione
  • Amino Acids
  • Acetyl Acid
  • Methyl Group

Question 3

Liver

Answer 3

• Major role in drug Metabolism / detoxification
  
  • ​production of bile / protein / cholesterol
  • store & release glucose
• Anatomy:
  
  • Central Vein System
  • Portal Triad
    
    • Potal vein
    • L/R Hepatic Arteries
    • L/R Bile ducts

Question 4

Liver Lobule

Answer 4

• Basic functional unit of liver
• Hexagonal cluster of Hepatocytes
  
  • centered around central vein
  • Portal Triad at each corner of the hexagon
    
    • Blood flows from portal vein/artery
    • –> sinusoids –>central vein
• Bile flows through bile canaliculi
  
  • –> in OPPOSITE direction, to bile duct

Question 5

Heapatic Acinus

Model based on blood circulation

Answer 5

• Model based on blood circulation
• Three zones based on proximity to blood supply, in order of INNER TO OUTER
  
  • 1- Periportal (blood high in oxygen/nutrients)
    
    • closest to portal vein
    • high toxins, higher metobilic rate
    • More gluconeogenesis / Fatty acid synth.
  • 2- Midzonal
  • 3- Centrilobular (lowest oxygen/nutrients)
    
    • first to show ischemic necrosis
    • closest to central vein
    • More CYP450 & Smooth ER
    • More xenobiotic metabolism

Question 6

Bile

Answer 6

• Dense viscous fluid w/
  
  • ​Bile salts / Phospholipids
  • Proteins / Cholesterol
• ​Purpose
  
  • Digestion / Absorption of LIPIDS from intestine
  • Route of elimination for many endogenous products, xenobiotics, & metabolites
• Bilary clearance
  
  • sometimes major route of elimination
  • direct elimination or after metabolism –> more polar metabolites
    *

Question 7

Enterohepatic Recycling

Answer 7

• Occurs in bile and intestine
• Conjugated (P2) metabolites are excreted in BILE
  
  • ​–> Cleaved to yield parent drug in INTESTINE
  • REABSORBED in Intestine
• ex. chloramphenicol

Question 8

Hepatocytes

Answer 8

• 70% of cells in the liver
• Constant renewal, 300-500day life span
• Found between sinusoidal space /bile canaliculi
• Organelles:
  
  • Rough ER: assemble proteins, drug metabolism
  • SMOOTH ER: Detox of Drugs, synthesis of lpids
  • Peroxisomes: FA oxidation
  • Golgi: Packages proteins
  • Mitochondria
  • Glycosomes: Glycolysis

Question 9

Endoplasmic Reticulum

Answer 9

• Most critical organelle for Drug Metabolism
• Smooth ER
  
  • preferential location for CYP Enzymes
• Largest organelle component in hepatocyte
• CYP450 INDUCERS –> INCREASE rate of ER membrane synthesis
• Rate of ER synthesis declines w/ age

Question 10

Phase 1 Metabolism

Oxidation

Answer 10

• Main Phase 1 Metabolism reaction
• Occurs mainly @Smooth ER of liver
  
  • ​also @kidney/intestine/lung
• Majority catalyzed by CYP450 superfamily
• Membrane bound / 57 different isoforms
• Majority for endogenous compound metabolism
  
  • steroids / bile acids
• 15 involved in metabolism of drugs

Question 11

CYP Naming

Answer 11

• CYP = Super Family
• CYP 1/2/3 = Family
• CYP2 C/D = Subfamily
• CYP2C 19 = member
• CYP2C19 *2 = allele

Question 12

Specialized Enzymes

Answer 12

• Enzymes act to INCREASE the rate of reaction by:
  
  • Approximation
  • Catalysis
    
    • LOWERS the ACTIVATION ENERGY
    • Stabilize transition state by non-covalent molecular forces
    • Facilitate e- transport
      
      • formation of reactive oxygen moeity

Question 13

Monooxygenases

Answer 13

• CYP450 Enzyme
• Insertion of 1 atom oxygen into an organic substrate while the other oxygen is reduced to WATER
• @active center of CYP450 catalysis is the Iron protoporphyrin 9 (heme group)
  
  • w/ a thiolate of the conserved cysteine residue as 5th ligand

Question 14

Michaelis-Menten

(Km)

Answer 14

• Cause of nonlinearity in drug metabolization
• Absorption / distribution / emlimination are all SATURABLE
  
  • = rate of reaction fails to increase in proportion to dose or concentration
• V_max= Maximum rate of metabolite formation
  
  • Directly proportional to total enzyme concentration
• EX. Phenytoin / Ethanol
  
  • Increase in dose –> decrease in hepatic clearance

Question 15

Phase 2 Enzymes

Answer 15

• Uridine Phosphate Glucuronosyltransferase:
  
  • in ER
• ​Sulfotransferase (in cytosol)
• N-Acetyltransferase (in cytosol)
• Glutathione-S-Transferase:
  
  • ​some in ER some cytosol

Question 16

Phase 2 Meatabolism

Answer 16

• Link a new group to parent drug or phase 1 metabolite
• Some lead to dramatic INCREASE in POLARITY**​
  
  • ​by Glucuronidation
    
    • ​introduce an IONIZED FXNal group
• Other conjugation just Terminate Activity
  
  • ​ex. methylation
• Protect against reactive metabolites
  
  • ex. glutathione conjugation