Effects of cisplatin-induced nephrotoxicity on gentamicin pharmacokinetics in rats

The effects of cisplatin-induced nephrotoxicity on the pharmacokinetics of a renally excreted antibiotic, gentamicin, were studied in F-344 rats. A single dose of gentamicin (30 mg/kg, iv) was given to different groups of rats alone, at the same time as, or on day 4, 7, 15, or 29 following cisplatin administration (6 mg/kg, iv). Cisplatin caused a significant decrease in gentamicin clearance and an elevation of gentamicin levels in plasma, kidneys, liver, and spleen at all the time points that were tested except concomitant administration. The maximum effect was seen when gentamicin was given on day 7 following cisplatin. The total clearance of gentamicin was reduced from 11 +/- 5 ml/(min X kg) in control rats to 2 +/- 2 ml/(min X kg) in cisplatin-treated rats. Twenty-four-hr urinary gentamicin excretion was decreased to 34 +/- 13% of the dose (control rats excreted 93 +/- 4% of dose). Rats given only gentamicin had a creatinine clearance of 5.9 +/- 0.6 ml/(min X kg), whereas those given gentamicin on day 7 following cisplatin had a creatinine clearance of 0.4 +/- 0.2 ml/(min X kg). Thus, cisplatin reduced gentamicin excretion in rats, resulting in elevated antibiotic levels in plasma and tissues for at least a month. Prior exposure to cisplatin may therefore be associated with an increased risk of toxicity from gentamicin, even when the antibiotic is administered in therapeutic doses. The effects of cisplatin on other renally excreted drugs need to be evaluated.