Abstract
NG-nitro-arginine (NNA) is known to exhibit stereoselective pharmacokinetics in which NG-nitro-d-arginine (d-NNA) has a faster clearance rate than NG-nitro-l-arginine (l-NNA) in anesthetized rats, and d-NNA undergoes unidirectional chiral inversion. It was postulated that chiral inversion of d-NNA was performed in a two-step pathway by d-amino acid oxidase (DAAO) followed by an unidentified transaminase. Such chiral inversion contributes (at least partially) to the pharmacokinetic stereoselectivity of NNA. This study used the selective inhibitor of DAAO, sodium benzoate, to test the above hypothesis. An i.v. bolus injection of d-NNA (32 mg/kg) and l-NNA (16 mg/kg) in conscious rats exhibited biphasic disposition with different pharmacokinetic parameters in a stereospecific manner (approximately 5–10-fold differences). Unidirectional chiral inversion of d-NNA but not l-NNA was found from these animals. In addition to its similar inhibitory effects on the d-NNA conversion and DAAO activity in kidney homogenates, sodium benzoate completely blocked chiral inversion of d-NNA and led to a smaller stereospecific difference, reflected by a nearly 50% reduction of d-NNA clearance and a 2-fold increase in t1/2 and area under the curve of d-NNA in benzoate-pretreated rats. The results suggest that DAAO plays an essential role in chiral inversion of d-NNA and chiral inversion contributes mostly to the pharmacokinetic stereospecificity of NNA.
Footnotes
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This work was supported by grants from the National Natural Sciences Foundation of China (30472052) and the Science Foundation of Shanghai Municipal Commission of Sciences and Technology (04DZ19214).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.011429.
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ABBREVIATIONS: NNA, NG-nitro-arginine; d-NNA, NG-nitro-d-arginine; l-NNA, NG-nitro-l-arginine; DAAO, d-amino acid oxidase; CEC, capillary electrochromatography; AUC, area under the curve; CL, clearance.
- Received June 18, 2006.
- Accepted December 12, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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