Abstract

The pharmacokinetics of a new carbapenem, DA-1131, were compared after i.v. administration of the drug, 50 mg/kg, to spontaneously hypertensive rats (SHRs) at 16 weeks of age (an animal model for human primary hypertension) and at 6 weeks of age (corresponding to the early phase of the development of hypertension, at which time blood pressure remains within the normotensive range) and their respective age-matched control normotensive Kyoto-Wistar rats (KW rats), and deoxycorticosterone acetate-salt-induced hypertensive rats at 16 weeks of age (an animal model for human secondary hypertension) and their age-matched control Sprague-Dawley rats. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) (4720 versus 7070 μg·min/ml) was significantly smaller, and the nonrenal clearance (CL_NR) (5.37 versus 3.57 ml/min/kg) was significantly faster in 16-week-old SHRs than those in their control KW rats. Similar results were also obtained from 6-week-old SHRs in AUC (3800 versus 4680 μg·min/ml) and CL_NR (7.73 versus 3.31 ml/min/kg). However, the values were reversed in 16-week-old deoxycorticosterone acetate-salt rats in AUC (5310 versus 3870 μg·min/ml) and CL_NR (2.57 versus 4.90 ml/min/kg). The significantly faster CL_NR of DA-1131 in both 6- and 16-week-old SHRs could be supported at least partly by the results of the in vitro metabolism with kidney homogenate and considerably greater total renal dehydropeptidase-I activity. The data above indicated that the significantly faster CL_NR of DA-1131 in 16-week-old SHRs than that in their age-matched control KW rats was due to any hereditary characteristics of SHRs and was not due to the hypertensive state itself.