The performed search strategy can be found in Supplementary Material?1. with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, genotyping is considered essential, therefore directing testing prior to initiating fluoropyrimidines. gene) increases the risk of fluoropyrimidine-induced toxicity. The gene activity score is currently based on the results of four variants, predicts DPD enzyme activity and is used to optimize an individuals starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). This manuscript provides an overview of the guideline development and summarizes the pharmacotherapeutic recommendations. In addition, a comparison to alternative recommendations is offered. The geneCdrug connection section includes background within the pharmacological mechanism of the interaction. In addition it also includes a list of the variants associated with toxicity and the method developed by DPWG for local translation of assay results into the gene activity score. This information may be useful for laboratories to select and design a genotyping assay and consequently determine the individuals predicted phenotype based on the genotype results. Consequently, the literature review assisting the gene encodes the enzyme DPD. is located on chromosome 1p21.3, and transcription variant 1 (“type”:”entrez-nucleotide”,”attrs”:”text”:”NM_000110.3″,”term_id”:”119943097″,”term_text”:”NM_000110.3″NM_000110.3) offers 26 exons, spanning ~900?kb . Over 160 different allele variants in have been recognized and explained in literature . According to the gnomAD internet browser , which consists of whole exome data of almost 140,000 individuals, consists of 2190 known variants. The prevalence of individual variants is low. The effect of genetic variance on DPD enzyme activity is not fully established for the majority of variants and the size of the effect can differ between variants. The rate of recurrence of the various variants and the connected phenotypes appears to vary significantly between nations and ethnic organizations. For example, in the Caucasian human population, ~3C5% has a partial DPD enzyme deficiency and 0.1C0.2% has a complete DPD enzyme deficiency. On the other hand, ~8% of the African American human population has a partial DPD enzyme Pyrroloquinoline quinone deficiency [15, 16]. GeneCdrug connection Pharmacological mechanism A schematic overview of fluoropyrimidine rate of metabolism is demonstrated in Fig.?1. The DPD enzyme is mainly found in liver, but also intestinal mucosa, leucocytes, tumour cells and additional tissues. Over 80% of 5-FU is definitely inactivated to 5-fluoro-5,6-dihydrouracil (DHFU) by DPD. The decreased metabolic activity of DPD prospects to improved intracellular concentrations of active metabolites of 5-FU . The improved intracellular concentration of 5-fluoro-2-deoxyuridine-5-monophosphate (FdUMP) increases the risk of toxicity such as diarrhoea, hand-foot syndrome, mucositis and Pyrroloquinoline quinone myelosuppression. Variants in the gene can result in reduced and even absent DPD enzyme activity, increasing the risk of severe toxicity. For example, 73% of the individuals with gene encoding DPD, DPD dihydropyrimidine dehydrogenase, DHFU 5,6-dihydrofluorouracil, FUPA fluoro-?-ureidopropionate, F-?-AL Fluoro-?-alanine, FUMP fluorouridine monophosphate, FUDP fluorouridine diphosphate, FUTP fluorouridine triphosphate, FUDR fluorodeoxyuridine, FdUMP fluorodeoxyuridine monophosphate, FdUDP fluorodeoxyuridine diphosphate, FdUTP fluorodeoxyuridine triphosphate, dUMP deoxyuridine monophosphate, dTMP deoxythymidine monophosphate, TS thymidylate synthase, gene encoding TS Since the genetic variation in only partially determines DPD enzyme activity, these recommendations for dose adjustment based on the predicted phenotype are no more than a tool that can be used to achieve the desired intracellular concentration of the active metabolite, to minimize risk of toxicity. The absence of tested variants does not eliminate the risk of toxicity. Pharmacokinetic dose adjustment (guided by IL1-ALPHA steady-state plasma concentrations or AUC) may also be useful to optimize the dose of 5-FU. This is, however, Pyrroloquinoline quinone currently not regularly utilized for capecitabine and tegafur, as they are primarily converted into 5-FU within cells. variants associated with toxicity The variants known or suspected to have an effect on DPD enzyme activity, are outlined in Table?1. These variants are mapped by the level of evidence for which association with toxicity has been established (columns) and the variants effect on DPD enzyme activity (rows). Novel variants in.