Opiate effects on 5-fluorouracil disposition in mice.

ABSTRACT

PURPOSE: This study was performed to investigate the effects of morphine on the disposition of 5-fluorouracil (5-FU). METHODS: Mice were injected subcutaneously (s.c.) with saline or morphine, 20 mg/kg. 5-FU was administered intravenously (i.v.) 30 min later as a single bolus or by constant infusion. Blood samples were obtained by orbital sinus puncture. Urine samples were obtained from the bladder after ligation of the external urethra. 5-FU concentrations in plasma and urine were determined by HPLC. RESULTS: Morphine markedly elevated plasma levels of 5-FU given at doses of 100 to 860 mg/kg. The plasma clearance rate of a bolus dose of 100 mg/kg 5-FU was significantly reduced from 54 to 28 ml/min per kg and the elimination half-life was increased from 6.9 to 12.2 min by prior administration of morphine. When 5-FU was infused at 0.5 mg/kg per min, morphine reduced its plasma clearance rate from 145 to 94 ml/min per kg. Mice made tolerant by prior morphine administration required higher doses of this opiate to raise 5-FU levels as well as to cause analgesia. The effects of morphine on 5-FU disposition were antagonized by naltrexone. Excretion of 5-FU in urine was not affected by morphine treatment. CONCLUSIONS: The plasma clearance rate of 5-FU in mice is significantly reduced by concomitant use of morphine. This effect of morphine is due to reduced hepatic elimination of 5-FU rather than to a decrease in its renal excretion.