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.

Animals↗

PubMedDate not supplied

Metabolism of pirprofen in man, monkey, rat, and mouse.

Pirprofen was well absorbed by man, rhesus monkey, rat, and mouse after oral administration of a solution of 14C-labeled compound. The major route of elimination of radioactivity in all four species was renal, mostly in the form of metabolites. Twelve metabolites of pirprofen, accounting for 80% or more of the urinary radioactivity, were identified in the urine of the four species. The metabolic pathways of pirprofen involved oxidation to the pyrrole analogue, and oxidation of the pyrroline double bond to an epoxide, followed by opening of the oxirane ring to a trans-diol derivative. Scission of the pyrroline or pyrrole ring was also observed, leading to the corresponding aniline-type metabolite, part of which underwent subsequent acetylation. Conjugation of the propionic acid functionality with glucuronic acid was found to be extensive in the mouse, rhesus monkey, and man, but not in the rat. Conjugation with taurine was also observed in the rat and mouse.

Adult↗