Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score.
The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in the metabolism of fluoropyrimidines. DPD deficiency occurs in 4-5% of the population and is associated with severe fluoropyrimidine-related toxicity. Several SNPs in DPYD have been described that lead to absent or reduced enzyme activity, including DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A/haplotype B3. Since these SNPs differ in their effect on DPD enzyme activity, a differentiated dose adaption is recommended. We propose the gene activity score for translating DPYD genotype into phenotype, accounting for differences in functionality of SNPs. This method can be used to standardize individualized fluoropyrimidine dose adjustments, resulting in optimal safety and effectiveness.
Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Linda M
LM
Henricks
Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
Carin A T C
CA
Lunenburg
Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Didier
D
Meulendijks
Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
Hans
H
Gelderblom
Department of Gastroenterology & Hepatology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Annemieke
A
Cats
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Jesse J
JJ
Swen
Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology & Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
Jan H M
JH
Schellens
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Henk-Jan
HJ
Guchelaar
D000483:Alleles; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000235:genetics / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011743:Pyrimidines / Q000493:pharmacokinetics
D000964:Antimetabolites, Antineoplastic; D011743:Pyrimidines; D042943:Dihydrouracil Dehydrogenase (NADP)
5-fluorouracil; DPYD; capecitabine; dihydropyrimidine dehydrogenase; fluoropyrimidines; gene activity score; individualized medicine; pharmacogenomics