The effect of different dosing schedules of UCN-01 on its pharmacokineticsand cardiohaemodynamics in dogs

7-Hydroxy-staurosporine (UCN-01) is now under development as a novel antica ncer drug. In clinical studies, different infusion schedules are being inve stigated in the USA and Japan. To examine the effect of different infusion schedules on the pharmacokinetics and cardiohaemodynamics of UCN-01, dogs w ere treated with UCN-01 as either a 3-h or a 24-h constant intravenous infu sion. Blood pressure and heart rate, together with UCN-01 concentrations du ring and after infusion, were monitored. To analyse the relationship betwee n the pharmacokinetics and cardiohaemodynamics of UCN-O1, the plasma concen tration of UCN-01 at the end of infusion (C (end)), the area under the plas ma concentration versus time curves (AUC(0-infinity)) and the mean residenc e time (MRT) were used. As indices of cardiohaemodynamic changes, the area under decreasing systolic blood pressure and increasing heart rate versus t ime curves (dAUC(pressure) and AUG(heart rate)) were calculated by the trap ezoidal method. For the 3-h (0. 22 and 0 .65 mgkg(-1)) and 24-h infusion (0 .81 to 6.48 mg kg(-1)), systolic and diastolic blood pressures fell after or during infusi ons, accompanied by a dose-dependent increase in heart rate for both infusi ons. During both infusion schedules, the plasma concentrations of UCN-01 gr adually increased and C-end showed a dose-proportional increase. After that , UCN-01 was eliminated bi-exponentially with an elimination half-life of 5 .14+/- 1. 12 to 8 32 +/- 1.80h. The total clearance (CLtotal) ranged from 0 .383 to 0666 +/- 0 149L h(-1) kg(-1) There was no significant difference i n these parameters among the doses in each infusion schedule, indicating th at UCN-01 has a linear pharmacokinetic profile over the dose range examined for each infusion, and there were also no significant differences between the 3-h and 24-h infusion except for MRT. The pharmacokinetic parameters of Cend, AUC0-infinity and slope(0-3h) exhibited a degree of correlation with the AUC(heart rate) in the 3-h infusion and correlated significantly with the dAUC(pressure) in the 24-h infusion. The MRT did not correlate with car diohaemodynamic changes during either infusion. In conclusion, the pharmacokinetic profile of UCN-01 after the shorter infu sion is similar to that after the longer one. However, a longer dosing peri od of UCN-O1 increased the residence time in comparison with the shorter in fusion. This may be due to the effect on the circulatory function in dogs.