QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.067116v1 310/2/469    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sun, Z. Articles by Bosron, W. F. Search for Related Content PubMed PubMed Citation Articles by Sun, Z. Articles by Bosron, W. F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB METHYLPHENIDATE

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Methylphenidate Is Stereoselectively Hydrolyzed by Human Carboxylesterase CES1A1

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana (Z.S., S.P.S., W.I.D., N.Y.K., Q.Z., T.D.H., W.F.B.); and Clinical and Administrative Pharmacy, University of Iowa College of Pharmacy, Iowa City, Iowa (D.J.M.)

Methylphenidate is an important stimulant prescribed to treat attention-deficit hyperactivity disorder. It has two chiral centers, but most current commercial formulations consist of the racemic mixture of the threo pair of methylphenidate isomers (d-, l-threo-methylphenidate). The d-isomer is the pharmacologically active component. Numerous studies reported that oral administration of the methylphenidate racemate undergoes first-pass, stereoselective clearance in humans with l-methylphenidate being eliminated faster than d-methylphenidate. Accordingly, the kinetics of hydrolysis of individual enantiomers by purified native and recombinant human liver carboxylesterases CES1A1 and CES2 and a colon isoenzyme CES3 were examined with a liquid chromatography/mass spectrometry assay. The expression of CES1A1, CES2, and CES3 in Sf9 cells and the methods for purification of the three isoenzymes are reported. CES1A1 has a high catalytic efficiency for both d- and l-enantiomers of methylphenidate. No catalytic activity was detected with CES2 and CES3 for either enantiomer. The catalytic efficiency of CES1A1 for l-methylphenidate (k_cat/K_m = 7.7 mM^–1 min^–1) is greater than that of d-methylphenidate (k_cat/K_m = 1.3–2.1 mM^–1 min^–1). Hence, the catalytic efficiency of CES1A1 for methylphenidate enantiomers agrees with stereoselective clearance of methylphenidate reported in human subjects. Both enantiomers of methylphenidate can be fit into the three-dimensional model of CES1A1 to form productive complexes in the active site. We conclude that CES1A1 is the major enzyme responsible for the first-pass, stereoselective metabolism of methylphenidate.

Address correspondence to: Dr. William F. Bosron, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 1345 W 16th St., L3–304, Indianapolis, IN 46202-2111. E-mail: wbosron{at}iupui.edu

This article has been cited by other articles:

				C. Jewell, C. Ackermann, N. A. Payne, G. Fate, R. Voorman, and F. M. Williams Specificity of Procaine and Ester Hydrolysis by Human, Minipig, and Rat Skin and Liver Drug Metab. Dispos., November 1, 2007; 35(11): 2015 - 2022. [Abstract] [Full Text] [PDF]

				M. A. Schiel, S.-l. Green, W. I. Davis, P. C. Sanghani, W. F. Bosron, and S. P. Sanghani Expression and Characterization of a Human Carboxylesterase 2 Splice Variant J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 94 - 101. [Abstract] [Full Text] [PDF]

				D. Tuerck, S. Appel-Dingemanse, M. Maboudian, F. Pommier, Y. Wang, and G. Sedek Dose-Proportional Pharmacokinetics of d-threo-Methylphenidate After a Repeated-Action Release Dosage Form J. Clin. Pharmacol., January 1, 2007; 47(1): 64 - 69. [Abstract] [Full Text] [PDF]

				S. K. Quinney, S. P. Sanghani, W. I. Davis, T. D. Hurley, Z. Sun, D. J. Murry, and W. F. Bosron Hydrolysis of Capecitabine to 5'-Deoxy-5-fluorocytidine by Human Carboxylesterases and Inhibition by Loperamide J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1011 - 1016. [Abstract] [Full Text] [PDF]