Vol. 285, Issue 1, 242-246, April 1998

Chronopharmacology of Granulocyte Colony-Stimulating Factor in Mice

Shigehiro Ohdo, Naoko Arata, Taku Furukubo, Eiji Yukawa, Shun Higuchi, Shigeyuki Nakano and Nobuya Ogawa

Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812 Japan (S.O., N.A., T.F., E.Y., S.H.); Department of Clinical Pharmacology and Therapeutics, Oita Medical University, Hasama-Machi, Oita 879-55, Japan (S.N.) and Department of Pharmacology, Ehime University School of Medicine, Shigenobu-Cho, Onsen-Gun, Ehime 791-02 (N.O.)

The role of the sensitivity of bone marrow cells to, and the pharmacokinetics of granulocyte colony-stimulating factor (G-CSF) on the rhythm of leukocyte-increasing effect was investigated in ICR male mice housed under a standardized light-dark cycle (lights on at 0700, off at 1900). A significant circadian rhythm was demonstrated for leukocyte counts at 24 hr after G-CSF (250 µg/kg, s.c.) injection at six different circadian times (P < .01). The leukocyte counts of mice given G-CSF at 0500, 0900, 1300 or 1700 were significantly higher than those of mice given G-CSF at 2100 (P < .01, respectively). The rhythmic pattern resembled overall the rhythm occurring after saline injection. In the comparison between leukocyte counts after G-CSF injection at 0700 and 1900, the time when leukocyte counts are equal in nondrugged state, the leukocyte counts at 24 hr after G-CSF (250 µg/kg, i.v.) injection were approximately 50% higher in mice injected with the drug at 0700 than at 1900 (P < .01). Bone marrow cultures obtained at two times of day resulted in different numbers of myeloid colonies even when treated with the same concentrations of G-CSF in vitro. The colony-forming activity of G-CSF was significantly more potent at 0700 than at 1900 (P < .01). The plasma G-CSF concentrations after G-CSF (250 or 5 µg/kg, i.v.) injection were significantly higher in mice receiving injections with the drug at 0700 than at 1900 (P < .05, respectively). The area under the curve and mean residence time were significantly larger in mice injected with the drug at 0700 than at 1900 (P < .01, P < .05, respectively). Our suggests that the rhythm of G-CSF activity is caused by that of the sensitivity of bone marrow cells to, and the pharmacokinetics of the drug.