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Chiral Analysis of d- and l-Ritalinic Acids in Biological Samples and the Stereoselective Metabolism of d- and l-Methylphenidate

Date

2001-11

Journal Title

Journal ISSN

Volume Title

Publisher

ORCID

Type

Degree Level

Masters

Abstract

This research work has been aimed at developing a chiral separation method for d- and l-ritalinic acids, and applying it to in vitro and in vivo studies on the enantioselective metabolism study of methylphenidate. Three chiral methods for the separation of d- and l-ritalinic acids have been investigated, and the al-acid glycoprotein method was demonstrated to be the best one for the quantitative analysis of ritalinic acids in biological samples. In addition, the in vitro enantioselective hydrolysis of methylphenidate was investigated using enzymes obtained from a commercial source, E-3128 (esterase from porcine liver), dog liver, human and dog plasma. Results clearly demonstrate that the enzymes from different sources exhibited differences in stereoselectivity. It appears that the esterase(s) in liver give preference to the 1-enantiomer of methylphenidate, and in contrast, the esterase(s) in plasma prefer the d-enantiomer. The in vivo pharmacokinetics was studied using four phases of intravenous administration of methylphenidate. It was demonstrated that there were stereoselective differences in the plasma concentrations and in the various pharmacokinetics parameters calculated. Results revealed that the clearance of the 1-methylphenidate was significantly greater than that of its d-antipode, which is consistent with previous reports obtained by measuring the remaining concentration of methylphenidate enantiomers. Combining with the in vitro results that there was the different enantiomeric preference in human plasma and the same preference in liver homogenates, it suggests that the hydrolysis of methylphenidate in humans mainly occurs in the liver. In conclusion, a new chiral method has been developed and validated for the quantitative analysis of enantiomeric ritalinic acids, and furthermore, it was successfully applied for the in vitro hydrolysis and in vivo pharmacokinetics of methylphenidate.

Description

Keywords

chiral separation method, d- and l-Methylphenidate

Citation

Degree

Master of Science (M.Sc.)

Department

Pharmacy and Nutrition

Program

Part Of

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DOI

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