Gene Variants Affecting Bioavailability of Drugs: Towards Individualized Immunosuppressive Therapy?

[摘要] Recent advances in molecular techniques and data analysis from the Human Genome Project (1) have identified numerous regions of genetic variability with over 60,000 of these residing in the coding region of human genes, both single-nucleotide polymorphisms (SNPs) and microsatellite regions, including genes relevant to organ transplantation (2). It is well recognized that large patient populations and individual patients may demonstrate large differences in drug bioavailability. The field of pharmacogenetics has provided important information concerning the role of gene variants in the response of transplant recipients to immunosuppressive therapy (3). It has been estimated that genetics can account for 20 to 95% of variability in drug disposition and effects (4). For example, in the case of azathioprine the genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) have a marked effect on its metabolism, and patients inheriting two mutant TPMT alleles require substantially lower doses to avoid severe hematopoietic toxicity (5). Pharmacogenetics, or the more genome-wide approach of pharmacogenomics taking polygenic effects into consideration, therefore, aim to identify the inherited basis for interindividual differences in drug response. There are numerous drug metabolizing enzymes, drug transport proteins, and drug targets, all of which may have genetic variants with potential functional effects on the pharmacokinetic of a specific drug.

[学科分类] 泌尿医学

[关键词] Bone marrow necrosis;Sickle cell disease;Hyperhemolysis syndrome