RT Journal Article
SR Electronic
T1 Inhibitory Effects of Benzoate on Chiral Inversion and Clearance of <em>N</em><sup>G</sup>-Nitro-Arginine in Conscious Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 331
OP 334
DO 10.1124/dmd.106.011429
VO 35
IS 3
A1 Xin Yan-Fei
A1 Zhou Xiang-Jun
A1 Lu Jie
A1 Wang Yong-Xiang
YR 2007
UL http://dmd.aspetjournals.org/content/35/3/331.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics