title: Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia.
abstract: OBJECTIVE
  Several constituents of cigarette smoke are known to interact with drug metabolizing enzymes and potentially affect treatment outcome with substrate drugs. The purpose of this study was to determine the effects of cigarette smoking on the pharmacokinetics and adverse effects of irinotecan.
  
  
  METHODS
  A total of 190 patients (49 smokers, 141 nonsmokers) treated with irinotecan (90-minute intravenous administration on a 3-week schedule) were evaluated for pharmacokinetics. Complete toxicity data were available in a subset of 134 patients receiving 350 mg/m2 or 600 mg flat-fixed dose irinotecan.
  
  
  RESULTS
  In smokers, the dose-normalized area under the plasma concentration-time curve of irinotecan was significantly lower (median, 28.7 v 33.9 ng x h/mL/mg; P = .001) compared with nonsmokers. In addition, smokers showed an almost 40% lower exposure to SN-38 (median, 0.54 v 0.87 ng x h/mL/mg; P < .001) and a higher relative extent of glucuronidation of SN-38 into SN-38G (median, 6.6 v 4.5; P = .006). Smokers experienced considerably less hematologic toxicity. In particular, the incidence of grade 3 to 4 neutropenia was 6% in smokers versus 38% in nonsmokers (odds ratio [OR], 0.10; 95% CI, 0.02 to 0.43; P < .001). There was no significant difference in incidence of delayed-onset diarrhea (6% v 15%; OR, 0.34; 95% CI, 0.07 to 1.57; P = .149).
  
  
  CONCLUSIONS
  This study indicates that smoking significantly lowers both the exposure to irinotecan and treatment-induced neutropenia, indicating a potential risk of treatment failure. Although the underlying mechanism is not entirely clear, modulation of CYP3A and uridine diphosphate glucuronosyltransferase isoform 1A1 may be part of the explanation. The data suggest that additional investigation is warranted to determine whether smokers are at increased risk for treatment failure.
authors.affiliation: Department of Medical Oncology, Erasmus MC University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: van der Bol
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Maja J A
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: André S Th
authors.initials: AS
authors.lastname: Planting
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Floris A
authors.initials: FA
authors.lastname: de Jong
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004347:Drug Interactions; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000188:drug therapy*; D012907:Smoking / Q000009:adverse effects*; D017211:Treatment Failure; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme