Abstract
Pharmacokinetic parameters of YH439 and its metabolites, M4, M5, and M7, were compared after iv administration of YH439 to rats (1–10 mg/kg), rabbits (1–10 mg/kg), and dogs (1–20 mg/kg) and oral administration of YH439 to rats (50–500 mg/kg) and dogs (0.5–2 g per whole body weight). After oral administration of YH439 to rats, theF values were 3.67, 1.33, and 0.859% for YH439 oral doses of 100, 300, and 500 mg/kg, respectively. However, the Fvalue increased significantly, 21.2%, after oral administration of YH439-contained mixed micelles (10 mg as free YH439) to rats due to increased water solubility of YH439. Species differences in the pharmacokinetics of YH439 and its metabolites were found. First, M7 was detected in both plasma and urine after both iv and oral administration of YH439 to dogs, whereas it was detected neither in rats nor in rabbits, indicating that considerable amount of M7 was formed from YH439 only in dogs. Second, the AUC (or AUC0→t) ratios of M4 to YH439 after iv administration of YH439 were 24.6–31.3, 42.2–49.2, and 2200–7640% for rats, rabbits, and dogs, respectively, indicating that formation of M4 after iv administration of YH439 was maximal in dogs. Third, the AUC (or AUC0→t) ratios of M5 to YH439 after iv administration of YH439 were 103–127, 2.93–3.31, and 92.4–158% for rats, rabbits, and dogs, respectively, indicating that formation of M5 after iv administration of YH439 was minimal in rabbits.
Footnotes
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Send reprint requests to: Myung G. Lee, College of Pharmacy, Seoul National University, San 56-1 Shillim-Dong, Kwanak-Gu, Seoul 151–742, South Korea.
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This study was supported in part by the Korea Ministry of Science and Technology (Han Project 4-1-1).
- Abbreviations used are::
- YH439
- [isopropyl 2-(1,3-dithioetane-2-ylidene)2-(N-4-methylthiazol-2-yl)carbamoylacetate]
- M7
- [isopropyl 2-(1,3-dithietane-2-ylidene)2-[N-[N′-(1-(+)-carboxyethyl)thioureido]carbonyl] acetate]
- M4
- [isopropyl 2-(1,3-dithioetane-2-ylidene)2-carboxylacetate]
- M5
- [isopropyl 2-(1,3-dithioetane-2-ylidene)2-[N-(4-carboxy-2-thiazolyl)carbamoyl] acetate]
- HPLC
- high-performance liquid chromatography
- DMSO
- dimethyl sulfoxide
- AUC
- total area under the plasma concentration-time curve from time 0 to time infinity
- AUC0→t
- AUC from time 0 to the last measured time
- CL
- time-averaged total body clearance
- AUMC
- first moment of AUC
- MRT
- mean residence time
- VSS
- apparent volume of distribution at steady state
- CLR
- time-averaged renal clearance
- CLNR
- time-averaged nonrenal clearance
- Ae(∞)
- total amount excreted in urine up to time infinity
- F value
- extent of dose absorbed into the general circulation
- Received May 29, 1997.
- Accepted October 8, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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