Pharmacogenetics of Drug-Metabolizing Enzymes: The Prodrug Hypothesis

Abstract

The hope of individualized drug therapy has been bolstered by the knowledge that drug-metabolizing enzymes can be affected by genetic polymorphisms. The initial flurry of potential examples has been muted somewhat by the failure of most predictions to be translated into clinical practice. Perhaps the only real example with reasonable evidence is that of azathioprine/6-mercaptopurine and thiopurine methyl-transferase. A few other examples such as tamoxifen, clopidogrel, irinotecan and warfarin warrant further discussion. An interesting feature of these drugs is that all except warfarin are prodrugs. We propose the hypothesis that prodrugs are over-represented in drugs that may be affected by genetic polymorphisms. Understanding this may assist our efforts to advance the field.

KEYWORDS::

• drug metabolism
• individualized dosing
• pharmacogenetics
• prodrug

Financial & competing interests disclosure

EJ Begg is a member of the Board of the Carney Centre of Pharmacogenomics. NA Helsby has been the recipient of a Cancer Society of New Zealand grant related to CYP2C19 pharmacogenetics in patients with cancer. BP Jensen is a recipient of a Carney Research Fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.