Improved pharmacodynamic assay for dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) activity determination in peripheral blood mononuclear cells of DPD deficient patients was hitherto inaccurate due to hemoglobin (Hb) contamination. We developed an improved method for accurate measurement of DPD activity in patients. RESULTS: DPD activity was determined by HPLC with online radioisotope detection using liquid scintillation counting. Hb was determined spectrophotometrically. Method accuracy and precision were significantly improved by using cumulative area of all peaks as IS. Peripheral blood mononuclear cell lysates from DPD deficient patients were highly contaminated with on average 23.3% (range 2.7-51%) of Hb resulting in up to twofold underestimated DPD activity. DPD activities were corrected for Hb contamination. The method was validated and showed good long-term sample stability. CONCLUSION: This method has increased specificity allowing accurate identification of DPD deficient patients.

Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration.

Dihydropyrimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome associated with potentially life-threatening toxicity following the administration of standard doses of 5-fluorouracil. This syndrome derives its importance from the fact that approximately 2 million patients receive the drug worldwide each year. Population studies have suggested that 4%-7% of the American population exhibit dose-limiting toxicity that might be associated with a genetic defect in the DPYD gene that encodes for the DPD enzyme. During the past several years it has become increasingly clear that genetics is a major determinant of the variability in drug response, accounting for the probability of drug efficacy and the likelihood of toxic drug reactions. This article briefly discusses the clinical presentation, laboratory diagnosis, pharmacokinetics, inheritance, and the clinical management options of DPD deficiency. The variability of DPD enzyme activity in population studies and the different DPYD alleles together with new phenotypic and genotypic methods of screening for DPD deficiency will also be reviewed.

Drug interaction ontology (DIO) for inferences of possible drug-drug interactions.

Drug Interaction Ontology (DIO) was developed for formal representation of pharmacological knowledge. It provides a fundamental framework for accumulation of reusable knowledge components in molecular pharmacology. Ontology was employed and implemented as a relational model. Some features include: 1) Drug-biomolecule interaction was assumed as a primitive knowledge element. 2) Symbolic representation was developed for drug-biomolecule interaction. Consequences of two conjugated units of interaction were defined by using symbols. These are applied for query development for identification of possible drug-drug interaction. 3) The triadic relationship model was developed as a ground model for bio-logical interactions and/or function, including semantic ones. One application of DIO is to support hypothesis generation of drug interaction by providing new hypotheses from a structured database storing literature information on known drug-biomolecule interactions. A knowledge base using DIO that contains information beginning with anti-cancer drugs is now under development. Detection of possible drug interaction was tested and its capacity to lead clinically known ones was confirmed. The system generated theoretically possible drug-drug interactions, which implies potential usefulness of new drugs to be tested before actual clinical application. In this paper, sorivudine and 5-fluorouracil mediated by dihydropyrimidine dehydrogenase are presented.

Cancer pharmacogenetics.

The large number of active combination chemotherapy regimens for most cancers has led to the need for better information to guide the 'standard' treatment for each patient. In an attempt to individualise therapy, pharmacogenetics and pharmacogenomics (a polygenic approach to pharmacogenetic studies) encompass the search for answers to the hereditary basis for interindividual differences in drug response. This review will focus on the results of studies assessing the effects of polymorphisms in drug-metabolising enzymes and drug targets on the toxicity and response to commonly used chemotherapy drugs. In addition, the need for polygenic pharmacogenomic strategies to identify patients at risk for adverse drug reactions will be highlighted.