Dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity in rats

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Abstract
Cardiac toxicity caused by doxorubicin (adriamycin) is a serious dose‐limiting factor in the clinical situation. However, the influence of doxorubicin dosing time has not been clarified from the viewpoints of cardiotoxic development and its mechanism. In this study, we have investigated the dosing time dependency of doxorubicin‐induced cardiotoxicity and bone marrow toxicity after repeated administration of doxorubicin in rats. When doxorubicin (5 mg kg−1, i.p.) was administered every seven days (total of 30 mg kg−1) at 3, 9, 15 or 21h after the light was turned on (HALO), toxic death was significantly higher in the 9 HALO treated group than the other groups. When doxorubicin was injected every seven days for 28 days at 9 or 21 HALO, we measured the levels of creatine kinase, malondialdehyde (MDA; an index of lipid peroxide), and glutathione peroxidase (GPx) as markers of cardiotoxicity. On days 14 and 28, creatine kinase levels were significantly higher in the 9‐HALO group compared with the 21‐HALO group (P < 0.01, respectively). On day 14, MDA levels increased significantly in the 9 HALO group compared with the 21 HALO group (P < 0.01). A single dose of doxorubicin was administered at 9‐h or 21‐h after the light was turned on to investigate the dosing‐time‐dependent difference of the pharmacokinetics. The area under the plasma time‐concentration curve showed a significant increase at 9 HALO compared with 21 HALO (P < 0.05). These results suggested that the dosing‐time‐dependent difference of cardiotoxicity induced by doxorubicin was closely related to the daily variation of doxorubicin pharmacokinetics. In conclusion, the choice of optimal dosing time based on the chronopharmacokinetics of doxorubicin may decrease the cardio‐toxicity and enable the practice of effective and safe chemotherapy of doxorubicin.