title: Randomized cross-over clinical trial to study potential pharmacokinetic interactions between cisplatin or carboplatin and etoposide.
abstract: OBJECTIVE
  Cisplatin and carboplatin are often used in combination with etoposide. In a randomized cross-over study, the potential interaction between the two platinum drugs and the metabolism of etoposide was explored. In vitro investigations using human liver microsomes were also performed.
  
  
  METHODS
  Etoposide was administered to 15 patients over 3 days, with the platinum drug administered on day 2. The alternate platinum drug was administered on the second course. The pharmacokinetics of etoposide were determined on all 3 days of each cycle. The effect of platinum drugs on etoposide metabolism by human liver enzymes was explored in vitro.
  
  
  RESULTS
  Neither cisplatin nor carboplatin coadministration affected the pharmacokinetics of etoposide during cycle 1. When carboplatin was administered on course 2, etoposide AUC was 8% higher on day 2 compared with day 1 or day 3 (for day 2 vs day 3, 95% CI: -0.72, -0.08 mg ml(-1) min). In contrast, cisplatin on course 2 increased the AUC of etoposide (28%) on day 3 (day 3 vs day 1, 95% CI: 0.67, 2.09 mg ml(-1) min), with no effect on day 2. In vitro carboplatin and cisplatin (10-100 microm) inhibited the metabolism of etoposide, if rat liver microsomes were preincubated (30 min) with NADPH and the platinum complexes. With human liver microsomes a small effect on etoposide metabolism, but not on catechol formation, was observed.
  
  
  CONCLUSIONS
  The interaction between etoposide and platinum drugs is small and, given the pharmacokinetic variability seen with etoposide, the clinical impact is unlikely to be significant.
authors.affiliation: Cancer Research Unit, Medical School, University of Newcastle, Newcastle General Hospital, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.forename: David J
authors.initials: DJ
authors.lastname: Porter
authors.forename: Imke
authors.initials: I
authors.lastname: Bartelink
authors.forename: Joy R
authors.initials: JR
authors.lastname: Nobbs
authors.forename: Michael
authors.initials: M
authors.lastname: Cole
authors.forename: Suzie
authors.initials: S
authors.lastname: Elliott
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: A Hilary
authors.initials: AH
authors.lastname: Calvert
authors.forename: Martin
authors.initials: M
authors.lastname: Highley
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D016190:Carboplatin / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000493:pharmacokinetics*; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005047:Etoposide / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D016190:Carboplatin; D002945:Cisplatin