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Glossary of Pharmacology 

Metabolic drug tolerance 

Definition: 

This term describes a situation where more drug is needed to achieve the same effect due to a pharmacokinetic change associated with chronic or repeated drug use. It is the result of altered metabolism as a function of time. This term is also known as pharmacokinetics or dispositional tolerance.  

Chronic consumption of ethanol is associated with metabolic drug tolerance. Following repeated consumption, the activity of the microsomal cytochrome P-450 enzymes is increased (microsomal induction), resulting in enhanced metabolism of ethanol and metabolic tolerance. Metabolic tolerance also contributes to opioid tolerance development. Studies have shown that increased concentration of morphine-3-glucoronide, a metabolite of morphine, can oppose the analgesic effects of morphine, contributing to tolerance (Dumas & Pollack, 2008)Other types of tolerance mechanisms are also involved in the decreased response to opiates following repeated exposure.  

Relevance: 

Drug tolerance has direct implication for clinical practice as patients might stop responding or respond less to a drug, leading to therapeutic failure or overdose. It also impacts drug development.  

As for other types of acquired drug tolerance, metabolic tolerance occurs upon the administration of repetitive doses. The time course for the development of tolerance can vary from minutes to weeks. If the loss of response occurs rapidly over a short period of time, this phenomenon is then called tachyphylaxis.  Downregulation (decreased number of receptors) and desensitization (decreased coupling efficiency) are mechanisms that account for drug tolerance and tachyphylaxis at the receptor level (also known as pharmacodynamic tolerance). More specifically to metabolic tolerance, changes in the metabolism or transport of a drug constitute the most common mechanisms underlying this condition. Changes in the rate of metabolism can occur as a result of altered expression or activity of the metabolizing enzymes with continuous drug exposure. Interestingly, a drug may affect its own metabolism by acting as a substrate and inducer of its metabolizing enzymes; a classic example of drug subjected to tolerance by this mechanism is ethanol.  

Metabolic tolerance can also occur as a result of reduced bioactivation of a drug due to enzymatic inhibition or reduced availability of substrate. For example, tolerance to nitroglycerin, a first-line treatment for angina pectoris and acute MI, is caused in part by the inactivation of the aldehyde dehydrogenase 2 enzyme which converts nitroglycerine into the vasodilator nitric oxide.  

Not to be mixed: 

The term metabolic tolerance also applies to adaptive metabolic changes in target cells that are driven by the continuous exposure to drugs. These adaptive changes are important in the context of antimicrobial resistance and resistance to cancer therapy.  

Examples: 

Below are examples of drugs that are known to be prone to metabolic tolerance: 

Drug or drug classes 

Possible PK mechanism(s) 

Nitroglycerine 

Inhibition of bioactivation, substrate depletion and others  

Barbiturates  

Induction of hepatic CYPs 1A2, 2C9, 2C19, and 3A4 

Alcohol (ethanol) 

Increased rate of metabolism – due to induction of CYP 2E1 


Teaching tips:  

Metabolic drug tolerance and the overall concept of tolerance are great points to discuss: 

  • Individual variability in drug response 
  • Therapeutic failure 
  • The risks associated with unnecessary drug exposure 
  • Individualized dose regimens  
  • Personalized medicine  

    Linked terms: tolerance, tachyphylaxis, genetic polymorphisms, metabolism

    References:

    Dumas, E. O., & Pollack, G. M. (2008). Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. The AAPS journal10(4), 537–551. https://doi-org.proxy1.lib.uwo.ca/10.1208/s12248-008-9056-1 

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