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Circadian Variation of 5-Fluorouracil Catabolism in Isolated Perfused Rat Liver¹

Division of Clinical Pharmacology [B. E. H., R. S., R. B. D.] and Biostatistics Unit [S-j. S.], Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294

The catabolism of 5-fluorouracil (FUra) was measured in isolated perfused rat liver (IPRL) at various times of the day. IPRLs were prepared from rats sacrificed at 3-h intervals and the elimination rate of FUra and FUra catabolites (i.e., rate leaving the IPRL in the effluent perfusate) following infusion of [³H]FUra was analyzed for circadian periodicity. Animals were housed under standardized conditions of light and dark and divided into two groups of 24 animals each. The first group was housed under "normal" light conditions (lights on from 6:00 a.m. to 6:00 p.m.; off from 6:00 p.m. to 6:00 a.m.), while the second group was housed under "reverse" light conditions (lights on from 10:00 p.m. to 10:00 a.m.; off from 10:00 a.m. to 10:00 p.m.). A circadian rhythm was observed in the elimination rate of FUra and FUra catabolites by both groups (P < 0.0001, Cosinor analysis). Under "normal" light conditions, peak and trough elimination rate of FUra was at 19 h after light onset (HALO; 183.8 ± 3.4 nmol/min/g liver) and 7 HALO (123.8 ± 3.4 nmol/min/g liver), respectively. There was a reciprocal relationship between the elimination rates of FUra and FUra catabolites with peak and trough values for FUra catabolites at 7 HALO (70.5 ± 3.6 nmol/min/g liver) and 19 HALO (17.5 ± 3.6 nmol/min/g liver), respectively. Animals housed under the "reverse" conditions of light and dark also exhibited a circadian pattern. Under the "reverse" conditions, the peak and trough elimination rate of FUra was at 18.5 HALO (170.0 ± 1.7 nmol/min/g liver) and 6.5 HALO (130.0 ± 1.7 nmol/min/g liver), respectively. The peak and trough elimination rate of FUra catabolites under these conditions occurred at 6.5 HALO (64.3 ± 2.2 nmol/min/g liver) and 18.5 HALO (29.7 ± 2.2 nmol/min/g liver), respectively. These results demonstrate that the elimination rate of FUra and FUra catabolites by IPRL varies over a 24-h period with a circadian rhythm in association with the light/dark cycle. Such a variation in the hepatic elimination rate of FUra in humans could result in a variation in the systemic level of drug during chemotherapy thus affecting the therapeutic efficacy of FUra. This study suggests that a circadian pattern in the hepatic catabolism of FUra needs to be considered when planning chemotherapeutic regimens with FUra.

¹ Supported in part by USPHS Grants CA-40530 and CA-13148.

² To whom requests for reprints should be addressed, at Box 600, Volker Hall, Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL 35294.

Received 6/22/89. Revised 9/ 5/89. Accepted 9/ 7/89.

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