Drug 3

• drug metabolism 


  chemical transformation of a drug into metabolites
• what mediates drug metabolism

  DMEs, found in the liver
• first pass metabolism (pre systemic)


  form metabolites to reduce bioavailability of orally administered drugs
• where does first pass metabolism occur

  gut wall and liver
• where are DMES found

  on basolateral membrane (facing gut) of E.R of hepatocytes
• phase 1 metabolism


  introduce functional groups, form metabolites
• phase 2 metabolism


  introduced functional group undergoes conjugation, attach polar endogenous molecule to functional group in drug (=conjugated metabolites)
• phase 1 metabolism oxidation example


  ethanol via ADH to toxic acetaldehyde, removing H
• prodrug definition


  molecules with little or no pharmacological activity that are converted in vivo to active parent drugs, used to increase oral drug delivery
• hydrolysis drug metabolism


  break ester or amide bods, often for prodrugs release active component
• hydrolysis drug metabolism example

  tenofovir disoproxil via esterase to tenofovir
• phase 1 metabolism reaction types

  oxidation, hydrolysis, dealkylation
• demethylation drug metabolism example 


  codeine via CYP2D6 to morphine (active ingredient)
• purpose of phase 2 metabolism

  increase hydrophilicity to facilitate excretion
• types of phase 2 metabolism reaction

  glucuronidation, sulfation, glutathione conjugation
• glucuronidation


  most common phase 2, UGT transfer glucuronic acid from UDP-glucuronic acid to the drug
• morphine glucuronidation 


  form morphine-6-glucuronide (active, minor) and morphine-3-glucuronide (inactive, major), enzyme = UGT
• glutathione


  endogenous antioxidant synthesised by body to protect against reactive chemicals
• glutathione conjugation 


  GST (glutathione S transferase) attach glutathione to drug of drug metabolite
• how is NAPQI detoxified

  glutathione conjugation (can be depleted = liver damage)
• 3 outcomes of drug metabolism

  increase molecular size and hydrophilicity, decrease elimination half life, alter pharmacological activity
• drug elimination half life

  the time taken for the plasma conc of drug to decrease by 50%, calculated in the elimination phase
• hydrophilic drugs fate

  renal (kidneys) excretion in urine, don't require metabolism
• lipophilic drugs fate


  hepatic metabolism in liver to make hydrophilic then some excreted in bile, others renal urine
• CYP 450

  a family of enzymes in drug metabolism, CYP form complex with P450 oxidoreductase, eventually metabolise drug
• 2 important CYP450 enzymes

  CYP3A4 - broad substrate specificity and CYP2D6 - most polymorphic and common for SNPs
• CYP induction


  drugs cause increase in CYP expression (drug interact with nuclear receptor to drive transcription of target gene)
• CYP induction example


  rifampicin to treat TB, a CYP3A4 inducer that increases rate of drug metabolism
• outcome of CYP induction

  reduced or lack of drug effect due to enhanced drug metabolism
• CYP 3A4 inducer


  rifampicin - used to treat TB
• rifampicin and warfarin 


  rifampicin decrease elimination half life of warfarin, decrease effectiveness as anticoagulant. Doesn't increase PT (time to form clot) for as long
• CYP inhibition


  drugs compete for active site of enzyme when co administered, can may be substrate for enzyme or not
• Competitive CYP inhibition 


  2 drugs compete for same CYP enzyme, metabolism of 1 is impaired
• Mechanism based inhibition


  drug metabolised by enzyme first, metabolite form complex with enzyme (covalent bonding) = deactivated enzyme so CYP enzymes can't be used for drug metabolism of target
• Mechanism based inhibition example of use

  ritonavir and cobicistat used in combination with other drugs to treat HIV infection
• outcomes of CYP inhibition

  exaggerated drug effects of toxicity due to reduced hepatic metabolism and lack of drug effects due to impaired metabolic activation of prodrug (need to be metabolised)
• 4 genotypes of CYP2D6 gene (metabolism)


  UM (ultra rapid)- 3 functional copies, EM (extensive) - wild type, 2 copies, IM (intermediate) - 1 functional 1 defective, PM - 2 defective copies
• UM effect of drugs on body

  little therapeutic effect, metabolised quickly so low plasma conc below window
• PM drug effects


  toxic effects, above window as struggle to metabolise without functional CYP
• ritonavir 


  CYP3A4 inhibitor (HIV protease inhibitor), inhibits metabolism of other protease inhibitor given with to prolong action of target protease inhibitor