title: Factors affecting human autopsy kidney-cortex and kidney-medulla platinum concentrations after cisplatin administration.
abstract: The objective of this study was to determine factors that affect cisplatin concentrations in human kidney cortex. We used flameless atomic absorption spectrophotometry to assay platinum in autopsy specimens of kidney cortex obtained from 83 cisplatin-treated patients. Concentrations were correlated with pretreatment factors and treatment conditions using univariate nonparametric statistics. Hierarchical stepwise multiple regression analyses of transformed (to normalize) data were then used to assess which factors were most important, controlling for other factors. Kidney-cortex platinum concentrations varied from 0 to 14.8 micrograms/g (median, 2.04 micrograms/g). The cumulative lifetime dose of cisplatin ranged from 10 to 1120 mg/m2 (median, 112 mg/m2). The time from the last cisplatin dose to death was < 1-609 days (median, 38 days). According to univariate statistics, factors that correlated (P < 0.05) with kidney-cortex platinum concentrations were the cisplatin dose per course, the pretreatment serum urea level, metoclopramide use (positive correlations), the time from the last cisplatin treatment to death, and the pretreatment serum albumin value (negative correlations). Factors that approached significance (0.05 < or = P < or = 0.10) were a history of hypertension, hyperbilirubinemia (positive), the serum calcium level, and phenytoin use (negative). In the multiple regression analysis, after controlling for the cisplatin dose per course and the time from the last treatment to death, only concurrent metoclopramide and phenytoin use entered the model. The hydration volume did not affect corrected kidney-cortex or kidney-medulla platinum concentrations. The following conclusions were reached: (1) it may be feasible to use lower hydration volumes than those used routinely, (2) any effect of hydration volume on cisplatin nephrotoxicity may not be mediated via a reduction in kidney-cortex platinum concentrations, (3) higher cisplatin doses might be tolerated with new 5-hydroxytryptamine-3 (5HT-3) antiemetics than were tolerated with metoclopramide, and (4) phenytoin should be tested for its ability to reduce cisplatin nephrotoxicity.
authors.affiliation: Ontario Cancer Treatment and Research Foundation, Ottawa Regional Cancer Centre, Canada.
authors.forename: D J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: C
authors.initials: C
authors.lastname: Dulberg
authors.forename: J M
authors.initials: JM
authors.lastname: Molepo
authors.forename: N Z
authors.initials: NZ
authors.lastname: Mikhael
authors.forename: V A
authors.initials: VA
authors.lastname: Montpetit
authors.forename: M D
authors.initials: MD
authors.lastname: Redmond
authors.forename: R
authors.initials: R
authors.lastname: Goel
mesh_terms: D001344:Autopsy; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D015999:Multivariate Analysis; D010984:Platinum / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D010984:Platinum; D002945:Cisplatin