title: Neurotoxicity and low paclitaxel clearance associated with concomitant clopidogrel therapy in a 60-year-old Caucasian woman with ovarian carcinoma.
abstract: OBJECTIVE
  The aim of the present case report was to describe a novel pharmacokinetic drug–drug interaction between the antiplatelet agent clopidogrel and the antineoplastic agent paclitaxel.
  
  
  METHODS
  The patient was identified in a previously described cohort of 93 patients with ovarian carcinoma treated with paclitaxel. The effect of clopidogrel acyl-β-D-glucuronide on the metabolism of paclitaxel was assessed in human liver microsomes. The analysis of clopidogrel in plasma and the quantification of paclitaxel and 6-hydroxypaclitaxel in in vitro samples were performed by liquid chromatography tandem mass spectrometry.
  
  
  RESULTS
  The patient was a 60-year-old female treated with an unknown dose of clopidogrel at the time of paclitaxel therapy. Clopidogrel was present in all three of the plasma samples obtained during paclitaxel dosing. Estimated unbound paclitaxel clearance was 238 l h−1, which was only 62% of the cohort geometric mean (385 l h−1; range 176–726). She was hospitalized three times, developed severe neuropathy and paclitaxel treatment was subsequently discontinued. In vitro, 30-min preincubation with 100 μM clopidogrel acyl-β-D-glucuronide inhibited the depletion rate of 0.5 μM paclitaxel by 51% and the formation rate of 6-hydroxypaclitaxel by 77%.
  
  
  CONCLUSIONS
  This is the first report of a clopidogrel–paclitaxel interaction, suggesting that clinically used doses of clopidogrel can reduce the cytochrome P450 2C8 (CYP2C8)-mediated systemic clearance of paclitaxel, leading to an increased risk of paclitaxel toxicity. Caution should be exercised whenever the simultaneous use of paclitaxel and clopidogrel cannot be avoided.
authors.forename: Troels K
authors.initials: TK
authors.lastname: Bergmann
authors.forename: Anne M
authors.initials: AM
authors.lastname: Filppula
authors.forename: Terhi
authors.initials: T
authors.lastname: Launiainen
authors.forename: Flemming
authors.initials: F
authors.lastname: Nielsen
authors.forename: Janne  T
authors.initials: J
authors.lastname: Backman
authors.forename: Kim
authors.initials: K
authors.lastname: Brosen
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D000077144:Clopidogrel; D065727:Cytochrome P-450 CYP2C8 / Q000378:metabolism; D065687:Cytochrome P-450 CYP2C8 Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000097:blood / Q000209:etiology*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D013988:Ticlopidine; D017239:Paclitaxel