Reviewing the mechanism of action of thiopurine drugs: towards a new paradigm in clinical practice.
The precise mechanism of action of thiopurine drugs remains unclear despite more than 40 years of use. Recent knowledge in the field of apoptosis and a better insight into, as well as a rapid increase in their use in several important areas of clinical medicine justify this appraisal. This is a review of the recent advances in the knowledge of their mechanism of action and is primarily intended to help clinicians understand the pharmacological properties of these drugs adequately and to find ways to improve their use in clinical practice. The parent compound is azathioprine (AZA), which is rapidly reduced in the presence of glutathione to 6-mercaptopurine (6-MP) and then metabolized into active metabolites with immune-modifier activity. Recent observations and new data indicate that AZA/6-MP could be considered as a "two-in-one" drug, providing a source of 6-thioguanine nucleotides (6-TGNs) and methylated metabolites, and that both compounds could contribute to its antiproliferative effects. This review will also focus on mechanisms that may help to explain a number of recent observations showing that myelotoxicity may occur in patients with high TPMT level or low 6-TGN rate. Our final proposal suggests that the immunosuppressive effects of these drugs are due to a balanced combination of antimetabolic and pro-apoptotic actions.
Cara
Carlos J
CJ
Scientific Department, Celltech Pharma, Madrid, Spain. carlos.cara@celltechgroup.com
Pena
Amado Salvador
AS
Sans
Miquel
M
Rodrigo
Luis
L
Guerrero-Esteo
Mercedes
M
Hinojosa
Joaquín
J
García-Paredes
Julio
J
Guijarro
Luis G
LG
D017209:Apoptosis; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D011687:Purines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013457:Sulfur Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D011687:Purines; D013457:Sulfur Compounds