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Metabolism of methylphenidate in dog and rat

Journal Article · · Drug Metab. Dispos.; (United States)
OSTI ID:5589419
; ; ;

The urinary metabolites of methylphenidate in the dog and rat were investigated. After oral administration of 14C-labeled methylphenidate, approximately 86% and 63% of the dose was recovered in the urine of the dog and rat, respectively. Less than 1% of the dose was excreted as unchanged drug. Metabolism involved oxidation, hydrolysis, and conjugation processes. The primary hydrolytic product was alpha-phenyl-2-piperidineacetic acid (24%, dog; 35-40%, rat). The primary metabolites of oxidation were methyl 6-oxo-alpha-phenyl-2-piperidineacetate (3%, dog; 1.5%, rat) and the glucuronide of alpha-(p-hydroxyphenyl)-2-piperidineacetic acid (10%, rat). The former also underwent extensive biotransformation, including: 1) hydrolysis to the lactam acid (27%, dog; 7-10%, rat) and subsequent carboxylic acid O-glucuronidation (15%, dog); or 2) hydroxylation at the 5-position (1%, dog; 2%, rat) and subsequent hydrolysis (4%, dog; 15-17%, rat); or 3) 5-O-glucuronidation (12%, dog). Additional minor metabolites from methyl-6-oxo-alpha-phenyl-2-piperidineacetate were the phenolic O-glucuronide of methyl alpha-(p-hydroxyphenyl)-6-oxo-2-piperidineacetate (1%, dog), and the 4-O-glucuronide of methyl 4-hydroxy-6-oxo-alpha-phenyl-2-piperidineacetate (1%, dog), and the taurine amide conjugate of alpha-(p-hydroxyphenyl)-6-oxo-2-piperidineacetic acid (1%, dog). Additional products from methylphenidate conjugation included methyl 1-carbamoyl-alpha-phenyl-2-piperidineacetate (1%, dog or rat) and its carboxylic acid hydrolysis product (1%, rat). The chirality of the major metabolites isolated from dog urine showed that metabolism was partially stereoselective in all investigated cases, except in the formation of alpha-phenyl-2-piperidineacetic acid.

Research Organization:
Research Department, CIBA-GEIGY Corporation, Ardsley, NY
OSTI ID:
5589419
Journal Information:
Drug Metab. Dispos.; (United States), Journal Name: Drug Metab. Dispos.; (United States) Vol. 9:5; ISSN DMDSA
Country of Publication:
United States
Language:
English

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Related Subjects

550201* -- Biochemistry-- Tracer Techniques
550501 -- Metabolism-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ACETIC ACID ESTERS
AMINES
ANIMALS
AZINES
CARBON 14 COMPOUNDS
CARBOXYLIC ACID ESTERS
DOGS
DRUGS
ESTERS
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
METABOLISM
METABOLITES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHARMACOLOGY
PIPERIDINES
PYRIDINES
RATS
RODENTS
TRACER TECHNIQUES
VERTEBRATES