Pharmacokinetic changes of a new carbapenem, DA-1131, after intravenous administration to spontaneously hypertensive rats and deoxycorticosterone acetate-salt-induced hypertensive rats.
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 microg x min/ml) was significantly smaller, and the nonrenal clearance (CLNR) (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 microg x min/ml) and CLNR (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 microg.min/ml) and CLNR (2.57 versus 4.90 ml/min/kg). The significantly faster CLNR 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 CLNR 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.
Kim
S H
SH
College of Pharmacy, Seoul National University, Seoul, South Korea.
Kim
W B
WB
Lee
M G
MG
D000818:Animals; D019540:Area Under Curve; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003900:Desoxycorticosterone; D004150:Dipeptidases / Q000378:metabolism; D006207:Half-Life; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D015780:Carbapenems; C099230:DA 1131; D003900:Desoxycorticosterone; D004150:Dipeptidases; C038937:dipeptidase