title: Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: a prospective cross-over drug-drug interaction study.
abstract: BACKGROUND
  Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan.
  
  
  METHODS
  Fourteen patients were treated with single agent irinotecan (600mg i.v., 90min) followed 3weeks later by a second cycle with concurrent use of omeprazole 40mg once daily, which was started 2weeks prior to the second cycle. Plasma samples were obtained up to 55h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS.
  
  
  RESULTS
  The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole.
  
  
  CONCLUSIONS
  Omeprazole 40mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.
authors.affiliation: Department of Medical Oncology, Erasmus MC – Daniel den Hoed Cancer Center, University Medical Center, Rotterdam, The Netherlands. jmvanderbol@gmail.com
authors.forename: Jessica M
authors.initials: JM
authors.lastname: van der Bol
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.forename: Floris A
authors.initials: FA
authors.lastname: de Jong
authors.forename: Esther
authors.initials: E
authors.lastname: van Meerten
authors.forename: Inge R H M
authors.initials: IR
authors.lastname: Konings
authors.forename: Mei H
authors.initials: MH
authors.lastname: Lam
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruijn
authors.forename: Erik A C
authors.initials: EA
authors.lastname: Wiemer
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009853:Omeprazole / Q000494:pharmacology*; D011446:Prospective Studies; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D054328:Proton Pump Inhibitors; D000077146:Irinotecan; D009853:Omeprazole; D002166:Camptothecin