PHARMACOKINETICS OF DA-125, A NEW ANTHRACYCLINE, AFTER INTRAVENOUS ADMINISTRATION TO SPONTANEOUSLY HYPERTENSIVE RATS AND DOCA-SALT-INDUCED HYPERTENSIVE RATS

Pharmacokinetic parameters-including tissue distribution, biliary excr etion, and urinary excretion of M1-M4- were compared after an intraven ous administration of DA-125 (a new anthracycline derivative; 20 mg/kg body weight) to male spontaneously hypersensitive rats (SHRs) at 16 w eeks (an animal model for human primary hypertension) and at 6 weeks ( corresponding to the early phase of the development of hypertension, a t which time blood pressure remains within the normotensive range) of age and their age-matched control Kyoto-Wistar rats, and male deoxycor ticosterone acetate-salt-induced Sprague-Dawley rats (DOCA-salt rats, an animal model for human secondary hypertension) at 16 weeks of age a nd their age-matched control Sprague-Dawley rats. Mean plasma concentr ations of both M2 and M4, and the resultant area under the plasma conc entration-time curve from time 0 to last measured time [AUCT; M2 (68.9 vs. 29.3 mu g-min/ml) and M4 (53.4 vs. 33.4 mu g-min/ml)], increased significantly in SHRs at 16 weeks of age, compared with their control rats. Similar results were also obtained from DOCA-salt rats at 16 wee ks of age, compared with their control rats. However, values were not significantly different between SHRs at 6 weeks of age and their contr ol rats. Previous data indicated that the significant increase in plas ma concentrations and the resultant AUCT values of both M2 and M4 in S HRs at 16 weeks of age were due to the hypertension state itself, and not to any hereditary characteristics of the SHRs, The significantly i ncreased plasma concentrations and the resultant AUCT values of M2 in both SHRs and DOCA-salt rats at 16 weeks of age were due to the signif icantly decreased biliary excretion of M2 and possibly to the increase d amount of aldo-keto reductase in the liver, However, the increase in the two aforementioned pharmacokinetic parameters in the case of M4 w ere possibly due solely to the increased amount of aldo-keto reductase in the liver.