| title: | The role of genetic and non-genetic factors in the pharmacokinetics and pharmacodynamics of thiopurine drugs |
|---|---|
| reg no: | ETF6691 |
| project type: | Estonian Science Foundation research grant |
| subject: |
3.1. Basic Medicine 3.2. Pharmacy, Pharmacology, Toxicology 3.3. Clinical Medicine |
| status: | accepted |
| institution: | TU Faculty of Medicine |
| head of project: | Kersti Oselin |
| duration: | 01.01.2006 - 31.12.2007 |
| description: | Thiopurine drugs are predrugs. Their immunosupressive and anticancer properties have been related to intracellularly formed thioguanine metabolites. Besides therapeutic effects myelotoxic side effects of thiopurine drugs have been associated with thioguanine nucleotides. Thiopurine methyltransferase (TPMT) is a phase II biotransformation enzyme which metabolizes thiopurines leading to the formation of inactive methyl metabolites. In clinical trials, erythrocytes TPMT activity has been found to correlate with the formation of cytotoxic metabolites and side effects. Therefore, it could be assumed that interindividual differences in efficacy and side effects of thiopurines are related to the variable TPMT activity. The project aims to investigate genetic and non-genetic factors which may alter TPMT activity and lead to variable efficacy and side effects of thiopurine drugs. We will determine TPMT activity in Estonian population. Previous in vitro studies have shown that TPMT activity could be modulated by GSH/GSSG ratio. To confirm these results in vivo we will also determine GSH/GSSG ratio. Contribution of genetic factors to interindividual differences will be studied by sequencing the entire TPMT gene. Thiopurine drugs and their metabolites are substrates for ABC transporters. The latter contribute to drug absorption and distribution. Therefore, the efficacy and side effects of thiopurines may be modulated by the activity of ABC transporters. To test this hypotheses we will perform a clinical trial in patients on thiopurine therapy and determine TPMT pheno- and genotype and correlate these results with functionally important SNPs in genes encoding ABC transporters. Patients on thiopurine therapy treated simultaneously with drugs which inhibit TPMT activity have higher risk for side effects. Previous studies have shown that salicylic acid and aminosalicylates inhibit TPMT activity. In vitro experiments with several non-steroidal anti-inflammatory drugs and selective COX2 inhibitors will be performed to investigate their potential to inhibit TPMT activity. |
| project group | ||||
|---|---|---|---|---|
| no | name | institution | position | |
| 1. | Kristi Kallassalu | |||
| 2. | Kersti Oselin | Tartu Ülikool | ||
| 3. | Tiina Ristimäe | |||
| 4. | Annika Vaarmann | |||
| 5. | Tiiu Vihalemm | |||