Lack of cisplatin-ranitidine kinetic interactions: in vivo study in children, and in vitro study using dog renal brush border membrane vesicles.
The interactions between cisplatin and organic ions have been extensively investigated in animal models for the potential to reduce cisplatin cellular uptake and resultant nephrotoxicity. To further investigate the beneficial interaction clinically, we studied the effects of the organic cation, ranitidine, on the renal handling of cisplatin in children. In parallel, we examined the effects of cisplatin on the uptake kinetics of organic cations and anions by brush border membrane vesicles (BBMV) prepared from dog renal cortex. The results indicate that: 1) there is no measurable effect of ranitidine on renal clearance of cisplatin in children; and 2) BBMV uptake of anionic p-aminohippurate, but not cationic N-methylnicotinamide, is inhibited by cisplatin at concentrations of <1 mM. These findings suggest that cisplatin may not share transport systems with organic cations to a clinically significant degree. Assuming that renal tubular transport is a prerequisite for cisplatin nephrotoxicity, the lack of apparent kinetic interactions between cisplatin and organic cations may preclude clinical use of organic cations as a modality to prevent cisplatin nephrotoxicity.
Ito
S
S
Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, Research Institute, University of Toronto, Ontario, Canada.
Weitzman
S
S
Klein
J
J
Greenberg
M
M
Lau
R
R
Atanakovic
G
G
Koren
G
G
D000293:Adolescent; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000009:adverse effects / Q000493:pharmacokinetics*; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007223:Infant; D007668:Kidney / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008871:Microvilli / Q000378:metabolism*; D011899:Ranitidine / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D011899:Ranitidine; D002945:Cisplatin