Opiate effects on 5-fluorouracil disposition in mice.
OBJECTIVE
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.
Li
Y
Y
Department of Internal Medicine, University of Kansas Medical Center, Kansas City 66160-7320, USA.
Looney
G A
GA
Kimler
B F
BF
Hurwitz
A
A
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000378:metabolism* / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology
D000701:Analgesics, Opioid; D000964:Antimetabolites, Antineoplastic; D009271:Naltrexone; D009020:Morphine; D005472:Fluorouracil