Effect of biological time on the determination of the LD50 of 5-fluorouracil in mice.

The LD50 was determined for 5-fluorouracil (FU) in mice at 11.00 and 23.00 h during one 24-hour period. These times were chosen because in mice kept on a light-dark cycle, with lights on from 06.00 to 18.00 h, the natural circadian rhythm in DNA synthetic activity in many different normal organs attains peak levels around 24.00 h (mid-dark) and through levels around 12.00 h (mid-light). The LD50 of FU, in milligrams per kilogram body weight, was much higher (450-500 mg/kg) at 11.00 than at 23.00 h (250-300 mg/kg). Since the biology of the living animal oscillates significantly on a daily or circadian basis, it is understandable that the degree of susceptibility or resistance to drugs should also fluctuate over the circadian period. Determination of the LD50 of a drug at that point in time when the animal is naturally resistant to that drug will result is a false appraisal of the toxic effects to the drug. To assess correctly the risk a drug poses, it should be tested at its time of maximal susceptibility in the living animal.