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 (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 μg·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 μg·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.
Footnotes
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Send reprint requests to: Myung G. Lee, College of Pharmacy, Seoul National University, San-56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea. E-mail: leemg{at}plaza.snu.ac.kr
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This work was supported in part by the Korea Ministry of Science and Technology (HAN Project), 1996–1997.
- Abbreviations used are::
- DA-1131
- (1R,5S,6S)-(2S,4S)-2-[(E)-3-methansulfonylamino-1-propenyl] pyrrolidine-4-ylthiol-6-[(R)-1-hydroxyethyl]-1-methyl-1carbapen-2-em-3-carboxylic acid
- DHP-I
- dehydropeptidase-I
- SHR
- spontaneously hypertensive rat
- KW
- Kyoto-Wistar
- DOCA
- deoxycorticosterone acetate
- AUC
- total area under the plasma concentration-time curve from time zero to time infinity
- MRT
- mean residence time
- CL
- time-averaged total body clearance
- CLR
- time-averaged renal clearance
- CLNR
- time-averaged nonrenal clearance
- VSS
- apparent volume of distribution at steady state
- Ae0—8 h
- total amount of unchanged DA-1131 excreted in 8-h urine
- Received October 16, 1998.
- Accepted February 10, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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