title: Impact of CYP3A5*3 and CYP2C8-HapC on paclitaxel/carboplatin-induced myelosuppression in patients with ovarian cancer.
abstract: The influence of genetic variants on paclitaxel-induced toxicity is of considerable interest for reducing adverse drug reactions. Recently, the genetic variants CYP2C8*3, CYP2C8-HapC, and CYP3A5*3 were associated with paclitaxel-induced neurotoxicity. We, therefore, investigated the impact of CYP2C8-HapC and CYP3A5*3 on paclitaxel/carboplatin-induced myelosuppression and neurotoxicity. Thirty-three patients from a prospective pharmacokinetics study were genotyped using pyrosequencing. Patients with variant alleles of CYP2C8-HapC were found to have significantly lower nadir values of both leukocytes and neutrophils (p < 0.05) than patients with the wild-type genotype. CYP3A5*3/*1 patients were shown to have borderline, significantly lower nadir values of leukocytes (p = 0.07) than *3/*3 patients. Combining the two genotypes resulted in a significant correlation with both leukopenia and neutropenia (p = 0.01). No effect of these genetic variants on neurotoxicity could be shown in this rather small study, but their importance for paclitaxel-induced toxicity could be confirmed.
authors.affiliation: Clinical Pharmacology, Division of Drug Research, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden; Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, SE-171 65 Solna, Sweden. henrik.green@liu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Gréen
authors.forename: Muhammad Suleman
authors.initials: MS
authors.lastname: Khan
authors.forename: Ingrid
authors.initials: I
authors.lastname: Jakobsen-Falk
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Åvall-Lundqvist
authors.forename: Curt
authors.initials: C
authors.lastname: Peterson
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D016190:Carboplatin / Q000009:adverse effects / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007958:Leukocyte Count; D007970:Leukopenia / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics*; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000009:adverse effects / Q000378:metabolism; D010597:Pharmacogenetics; D010641:Phenotype; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D016190:Carboplatin; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel