Clinical pharmacology and pharmacogenetics of thiopurines

@article{Sahasranaman2008ClinicalPA,
  title={Clinical pharmacology and pharmacogenetics of thiopurines},
  author={Srikumar Sahasranaman and Dan Howard and Sandip K. Roy},
  journal={European Journal of Clinical Pharmacology},
  year={2008},
  volume={64},
  pages={753-767}
}
The thiopurine drugs—azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine—are widely used to treat malignancies, rheumatic diseases, dermatologic conditions, inflammatory bowel disease, and solid organ transplant rejection. However, thiopurine drugs have a relatively narrow therapeutic index and are capable of causing life-threatening toxicity, most often myelosuppression. Thiopurine S-methyltransferase (TPMT; EC 2.1.1.67), an enzyme that catalyzes S-methylation of these drugs, exhibits… 
On therapeutic drug monitoring of thiopurines in inflammatory bowel disease; pharmacology, pharmacogenomics, drug intolerance and clinical relevance.
TLDR
Suggestions to optimize thiopurine therapy in the treatment of inflammatory bowel diseases are provided and pharmacologically active 6-thioguanine nucleotide concentrations is most widely used.
Metabolite monitoring to guide thiopurine therapy in systemic autoimmune diseases
TLDR
Thiopurine metabolite monitoring shows wide variability in 6-TGN levels among patients treated with weight-based thiopurines for systemic autoimmune diseases, and dose adjustment should be studied prospectively.
ATIONS OF THIOPURINES IN THE TREATMENT OF INFL AMMATORY BOWEL DISEASE
TLDR
This review focuses on pharmacology and drug monitoring of thiopurines and provides an overview of clinically and scientifically challenging topics concerningThiopurine therapy in IBD treatment.
Pharmacogenomics of Thiopurine-Induced Toxicity in Children
TLDR
In patients, exhibiting low TPMT activity dosage of thiopurine drugs is reduced, or an alternate therapy is considered to avoid adverse drug reactions like myelosuppression, hematologic toxicity, and hypoplasia of the bone marrow.
Optimizing Thiopurine Therapy with a Xanthine Oxidase Inhibitor in Patients with Systemic Autoimmune Diseases: A Single-Centre Experience.
TLDR
Optimizing thiopurine therapy with an XOI may be a safe and effective strategy for patients with systemic autoimmune diseases.
Clinical relevance of thiopurine S-methyltransferase gene polymorphisms.
TLDR
This minireview summarizes results of studies assessing the role of genetic polymorphisms in the gene encoding TPMT and their relationship to the toxicity of thiopurines.
Thiopurine therapy in inflammatory bowel disease
TLDR
Factoring their proven efficacy over a broad range of clinical scenarios within Crohn’s disease and ulcerative colitis together with their overall safety profile and convenient and inexpensive once-daily oral administration, azathioprine and 6-mercaptopurine remain among the mainstays of Crohn's disease and Ulcerative Colitis therapy.
Thiopurine methyltransferase genotype and thiopurine S-methyltransferase activity in Greek children with inflammatory bowel disease
TLDR
The findings suggest that carriers of at least one variant allele and both intermediate and absent TPMT activity have an increased risk of developing thiopurine-induced myelotoxicity compared with individuals with normal genotype and T PMT activity.
Individually administered or co-prescribed thiopurines and mesalamines for inflammatory bowel disease.
TLDR
Interaction between basic research and clinical practice has continued to inform indications and refine the prescriptions of mesalamines and thiopurines; these have not been restrained by the advent of the novel biological molecules with anti-cytokine activity.
...
...

References

SHOWING 1-10 OF 163 REFERENCES
Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy?
Thiopurines [azathioprine (AZA), 6-mercaptopurine (6-MP) and thioguanine (6-TG)] have a well-established role as immunosuppressive agents in a variety of chronic inflammatory conditions,
The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics.
TLDR
TPMT genotype is correlated with erythrocyte and leukemia blast cell TPMT activity and associated with a risk of toxicity after thiopurine therapy, and target starting doses for mercaptopurine based on T PMT genotypes are defined.
Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase.
  • R. Weinshilboum
  • Biology, Medicine
    Drug metabolism and disposition: the biological fate of chemicals
  • 2001
TLDR
The TPMT genetic polymorphism represents a model system for the way in which basic pharmacogenetic information is developed and applied to clinical medicine as well as a target for clinically significant drug interactions.
Thiopurine Treatment in Inflammatory Bowel Disease
TLDR
Clinical pharmacological aspects of thiopurines in the treatment of chronic inflammatory bowel disease (IBD) are summarised and comprehensive analyses including metabolic patterns and genome-wide profiling in patients with azathioprine/mercaptopurine treatment are required to identify novel candidate genes.
Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing.
TLDR
Clinical pharmacological aspects of thiopurines in the treatment of chronic inflammatory bowel disease (IBD) are summarised and use of azathioprine/mercaptopurine for induction and maintenance of remission in corticosteroid-dependent or cortic Fosteroid-refractory IBD, particularly Crohn's disease, is evidence based.
Molecular Diagnosis of Thiopurine S-Methyltransferase Deficiency: Genetic Basis for Azathioprine and Mercaptopurine Intolerance
TLDR
An inverse correlation between TPM activity and accumulation of the active thioguanine nucleotide metabolites of mercaptopurine and azathioprine in erythrocytes is established and two mutant alleles that are associated with TPM deficiency are isolated and characterized.
Pharmacogenetics of Thiopurine S-Methyltransferase and Thiopurine Therapy
  • W. Evans
  • Biology, Medicine
    Therapeutic drug monitoring
  • 2004
TLDR
This review uses the TPMT polymorphism and thiopurine therapy to illustrate the potential of pharmacogenomics to elucidate genetic determinants of drug response, and optimize the selection of drug therapy for individual patients.
The clinical pharmacology of 6-mercaptopurine
  • L. Lennard
  • Biology, Medicine
    European Journal of Clinical Pharmacology
  • 2005
TLDR
Both mercaptopurine and azathioprine have cytotoxic and immunosuppressive properties that are variously due to the inhibition of the synthesis of proteins, DNA, and RNA, with additional effects attributable to the reactive thiot group.
Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia
TLDR
There are emerging data that TPMT genotype may influence the risk of secondary malignancies, including brain tumors and acute myelogenous leukemia, and ongoing studies aim to clarify the influence of T PMT on thiopurine efficacy, acute toxicity, and risk for delayed toxicity.
No Induction of Thiopurine Methyltransferase During Thiopurine Treatment in Inflammatory Bowel Disease
TLDR
The aim of this study was to study the role of TPMT and ITPA 94C > A polymorphisms for the development of adverse drug reactions, and to follow thiopurine naïve patients with ulcerative colitis or Crohn's disease.
...
...