Cisplatin-induced vomiting depends on circadian timing

We examined whether the clock time of cisplatin plus antiemetic and diureti c administration affects the amount of cisplatin-associated emesis and seve rity of renal toxicity. We treated 22 patients with urogenital cancer with two courses of chemotherapy containing 70 mg/m(2) of cisplatin. Cisplatin t ogether with furosemide was administered in the morning (05:00) or evening (17:00) during two courses I month apart in a crossover fashion. Ondansetro n was given either before or after cisplatin to control nausea and vomiting . The number of vomiting episodes, serum creatinine, serum urea nitrogen (B UN), creatinine clearance, and urinary beta -N-acetyl glucosamidase (NAG) c oncentration were evaluated before and after each treatment course. Regardl ess of the timing of ondansetron, morning compared to evening cisplatin was always associated with greater vomiting in the first treatment course. How ever, prophylactic administration of ondansetron markedly diminished the im pact of the clock time of cisplatin administration. Serum creatinine transi ently decreased rather than increased 14 days after cisplatin and furosemid e administration, while NAG excretion increased 3 days after cisplatin and furosemide administration. In the first course, serum creatinine levels wer e similar regardless of the clock time of cisplatin and furosemide administ ration. However, in the second course, serum creatinine rose in patients gi ven evening cisplatin and furosemide, while it remained unchanged in those given morning cisplatin and furosemide. Moreover, the first course morning cisplatin and furosemide treatment was associated with less change in NAG e xcretion (less kidney toxicity) than the first course of evening cisplatin and furosemide treatment. The second course evening cisplatin and furosemid e treatment was associated with an increase in NAG excretion compared to th e first course of treatment, while morning cisplatin and furosemide treatme nt in the second course showed less change in NAG excretion compared to the first course. The clock time of cisplatin administration had an impact on the frequency of emesis. Prophylactic ondansetron, however, diminished the time-of-day dependency of cisplatin-induced vomiting. Administration of cis platin and furosemide in the morning rather than evening appears to cause l ess renal damage, and this damage may be further reduced with aggressive hy dration and routine administration of furosemide.