The use of probenecid as a chemoprotector against cisplatin nephrotoxicity.
Probenecid inhibits cisplatin (CP) secretion in humans and protects against CP-induced nephrotoxicity in rats. The authors conducted a Phase I trial of escalating doses of CP using probenecid as a chemoprotector. Fifty-four courses of CP at doses ranging from 100 to 160 mg/m2 were given by 24-hour infusion to 36 patients. There was no renal impairment at any dose. Ototoxicity, however, became the dose-limiting toxicity; 14 patients experienced a 20 or greater decibel (dB) loss. Seven percent of courses were associated with a leukocyte count of less than 1.5 x 10/microliters, and 19% with a platelet count of less than 50 x 10(3)/microliters. Only three patients developed neurotoxicity. Correlating pharmacokinetic data and toxicity, the authors found that high cumulative dose, area under the curve (AUC) for unbound platinum, and cumulative AUC were associated with ototoxicity and peripheral neuropathy. It was concluded that probenecid may protect against CP nephrotoxicity and warrants further investigation. Its unique mechanism of action and lack of toxicity make it ideal to combine with other chemoprotectors.
Jacobs
C
C
Department of Medicine, Stanford University School of Medicine, California 94305-5306.
Kaubisch
S
S
Halsey
J
J
Lum
B L
BL
Gosland
M
M
Coleman
C N
CN
Sikic
B I
BI
D000328:Adult; D000368:Aged; D002945:Cisplatin / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D003404:Creatinine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D005260:Female; D034381:Hearing Loss / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D011339:Probenecid / Q000627:therapeutic use*; D001613:beta 2-Microglobulin / Q000652:urine
D001613:beta 2-Microglobulin; D003404:Creatinine; D011339:Probenecid; D002945:Cisplatin