title: Genotypes Affecting the Pharmacokinetics of Anticancer Drugs.
abstract: Cancer treatment is becoming more and more individually based as a result of the large inter-individual differences that exist in treatment outcome and toxicity when patients are treated using population-based drug doses. Polymorphisms in genes encoding drug-metabolizing enzymes and transporters can significantly influence uptake, metabolism, and elimination of anticancer drugs. As a result, the altered pharmacokinetics can greatly influence drug efficacy and toxicity. Pharmacogenetic screening and/or drug-specific phenotyping of cancer patients eligible for treatment with chemotherapeutic drugs, prior to the start of anticancer treatment, can identify patients with tumors that are likely to be responsive or resistant to the proposed drugs. Similarly, the identification of patients with an increased risk of developing toxicity would allow either dose adaptation or the application of other targeted therapies. This review focuses on the role of genetic polymorphisms significantly altering the pharmacokinetics of anticancer drugs. Polymorphisms in DPYD, TPMT, and UGT1A1 have been described that have a major impact on the pharmacokinetics of 5-fluorouracil, mercaptopurine, and irinotecan, respectively. For other drugs, however, the association of polymorphisms with pharmacokinetics is less clear. To date, the influence of genetic variations on the pharmacokinetics of the increasingly used monoclonal antibodies has hardly been investigated. Some studies indicate that genes encoding the Fcγ-receptor family are of interest, but more research is needed to establish if screening before the start of therapy is beneficial. Considering the profound impact of polymorphisms in drug transporters and drug-metabolizing enzymes on the pharmacokinetics of chemotherapeutic drugs and hence, their toxicity and efficacy, pharmacogenetic and pharmacokinetic profiling should become the standard of care.
authors.affiliation: Department of Clinical Pharmacy, Isala, Zwolle, The Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: Bertholee
authors.affiliation: Department of Clinical Pharmacy, Isala, Zwolle, The Netherlands.
authors.forename: Jan Gerard
authors.initials: JG
authors.lastname: Maring
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, F0-220, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. a.b.vankuilenburg@amc.uva.nl.
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation / Q000187:drug effects / Q000502:physiology; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D010597:Pharmacogenetics / Q000379:methods / Q000639:trends; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects / Q000235:genetics*; D000099148:UGT1A1 Enzyme
chemical_list: D000970:Antineoplastic Agents; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme