Canterbury DHB

Prodrugs: Metabolism and Dosing

• Prodrugs are drugs that exert their effect largely through an active metabolite. Drug effect is determined by the concentration of the active metabolite, which depends on the enzymatic metabolism of the parent drug to the active metabolite.

  

• Decreased activity of the metabolising enzyme results in less active metabolite and higher risk of therapeutic failure.
• Increased enzyme activity results in more active metabolite and higher risk of toxicity.
• The metabolic pathway may be affected by inhibition or induction (e.g. dug interactions) and pharmacogenetics.
• Drug activity is also affected by clearance of the active metabolite itself (e.g. morphine-6-glucuronide, an active metabolite of codeine, is cleared renally, so consider dose adjustment of codeine in renal failure).

  Prodrug	Metabolising enzyme/s	Active Metabolite
  codeine	CYP2D6	morphine
  tamoxifen	CYP2D6	endoxifen
  clopidogrel	CYP2C19	thiol metabolite
  azathioprine/6MP	TPMT	6-thioguanines (6TG)
  ACE inhibitors (e.g. perindopril)	esterases	perindoprilat

Prodrugs and Pharmacogenetics

• Codeine and CYP2D6: Codeine is active largely through production of morphine via CYP2D6. Approximately 5-10% of Caucasians, 5% of Māori and 1-2% of Asians and Polynesians, are slow metabolisers and fail to produce meaningful concentrations of morphine. This explains apparent codeine ‘resistance’ in some people. On the other hand, ultrametabolisers experience excessive morphine effect through increased metabolic conversion.
• Azathioprine, 6-mercaptopurine (6MP), and TPMT: Azathioprine converts to 6MP which is metabolised by several steps to the active 6-thioguanines (6TG). The main enzyme that determines how much 6TG is produced is TPMT. For more information, see the Thiopurine Dosing Guidelines in Immunosuppresive Therapy.
• Tamoxifen and CYP2D6: Similar to codeine, tamoxifen requires activation by CYP2D6, in this case to endoxifen. Slow metabolisers may have a poorer response. There are arguments for genotype testing for CYP2D6 prior to therapy and for Therapeutic Drug Monitoring (TDM). However, these are not widely practised.
• Clopidogrel and CYP2C19: Clopidogrel requires activation to a thiol metabolite, which involves CYP2C19. There is quite a strong argument for genotype testing. However, these are not widely practised.

Prodrugs and Drug-Drug Interactions

• People who are pharmacogenetically ‘normal’ metabolisers may become:
  • slow metabolisers if the converting enzyme is inhibited
  • faster metabolisers if the converting enzyme is induced
• For more information, see the Activation of prodrugs affected by CYP induction/inhibition bulletin.

must be prescribed or recommended by a consultant.

Topic Code: 93325