The pharmacokinetics of 11-Hydroxyaclacinomycin X (HAMX), a novel anthracycline, were investigated after intravenous bolus administration in mice, rats, rabbits and dogs. Based on animal data, we predicted the following human pharmacokinetic parameters using allometric scaling: 24.1 and 6.99 mL/min/kg for total body clearance (CLt) using simple and maximum life-span potential (MLP)-corrected allometry, respectively; 5.72 L/kg for steady-state volume of distribution (Vdss ). The corresponding allometric equation were CLt = 45.896W0.8452, CLt × MLP = 31.175W1.1405 and Vdss = 10140x0.8653. These allometric equations were extrapolated to predict CLt and Vdss in human based on 70 kg body weight. We also predicted human parameters using species-invariant time transformations (equivalent time, kallynochrons, apolysichrons and dienetichrons). The values of Vdss (15.4-19.4 L/kg) obtained using invariant time transformations were larger than those obtained using simple allometry. However, the lowest CLt (17.0 mL/min/kg) derived usi ngdienetichrons was comparable to that obtained using simple allometry. The results of this study also indicated that the predicted human CLt generated using MLP-corrected allometry can be used for the selection of a safe dose for studies in healthy adult human volunteers. These results suggest that such approaches may be useful in designing pharmacokinetic studies for novel anthracyclines. The preliminary parameter values may be useful in designing early pharmacokinetic studies of HAMX in humans. The results could also be used to determine the safe dose for the therapeutics in various animals.

We investigated free radical reactions in lung of living mice using an in vivo electron spin resonance (ESR) spectrometer and nitroxyl radical as a probe. When an aqueous solution of nitroxyl probe was trans-tracheally administered into lung of living mice, a sharp triplet signal was observed at the chest of the mice. The signal showed a gradual decrease with time, obeying first-order kinetics. Signal decay rates of carbamoyl-PROXYL and carboxy-2,2,6,6-tetramethyl-piperidine-N-oxyl were faster than those of CAT-1 and carboxy-PROXYL. The mechanism of signal decay may be attributed to (i) reaction with reactive oxygen species such as ·OH, (ii) transfer into blood circulation, or (iii) reduction by compounds continuously supplied. However, little is known about the clearance mechanism of the nitroxyl probe in lung. To evaluate the disappearance of the ESR signal of the nitroxyl probe in lung, in vivo ESR spectra in chest of mice was recorded after trans-tracheal administration of an aqueous high concentrate solution of nitroxyl probe. A broad signal from the chest was observed immediately after administration due to Heisenberg spin exchange interaction. A sharp triplet signal was superimposed on the broad signal and the appearance of a triplet signal was followed by disappearance of the broad one. Peak-to-peak line width of the sharp signal was almost the same as that after intravenous administration. A distinct signal was detected in blood collected 10 min after trans-tracheal administration of nitroxyl probe. The observations indicate the transfer from lung to blood circulation and its contribution to clearance of probe in lung. Appearance of a sharp signal in blood after trans-tracheal administration was dependent on the kind of nitroxyl probe, showing a different transfer rate from lung to blood.