Ritalinic acid

Black, R. Henion, J. High-throughput selected reaction monitoring liquid chromatography-mass spectrometry determination of methylphenidate and its major metabolite, ritalinic acid, in rat plasma employing monolithic columns. J Chromatogr B Anal Technol Biomed Life Sci 2003, 783, 73-83. 

Metabolism - Dexmethylphenidate is metabolized primarily to c/- -phenyl-piperidine acetic acid (also known as c/-ritalinic acid) by de-esterification. This metabolite has little or no pharmacological activity. 

Mefabo//sm - Methylphenidate is metabolized rapidly primarily via deesterification to alpha-phenyl-piperidine acetic acid (PPA or ritalinic acid). The metabolite has little or no pharmacologic activity. 

Scheme 17.7. Separation of (+) threo and erythro ritalinic acids 22 and 23.

Chan, Y.P., Swanson, J.M., Soldin, S.S., Thiessen, JJ-, and Macleod, S.M. (1983) Methylphenidate hydrochloride given with or before breakfast II. Effects on plasma concentration of methylphenidate and ritalinic acid. Pediatrics 72 56-59. 

Methylphenidate is readily absorbed and produces peak plasma levels in approximately 2 hr (immediate-release formulation). The duration of action is 3-6 hr for the immediate-release and 8 hr for the sustained-release formulation. Approximately 90% of methylphenidate is excreted in the urine as metabolites (80% is ritalinic acid) and the remainder as unchanged drug (26,36). 

High Pressure Liquid Chromatography. In serum methylphenidate and ritalinic acid, sensitivity 20 ng/ml, UV detection—S. J. Soldin et al., Clin. Chem., 1979, 25,401-404. 

Disposition in the Body. Readily absorbed after oral administration. About 80% of a dose is excreted in the urine in 24 hours, of which 60 to 80% is ritalinic acid and 5 to 12% is 6-oxo-a-phenylpiperidine-2-acetic acid only a small amount is excreted as unchanged drug. 

Following a single oral dose of 20 mg to 2 subjects, peak plasma concentrations of 0.013 and 0.058 pg/ml were attained in 3 hours ritalinic acid concentrations averaged 0.22 pg/ml at the same time (R. M. Milberg et al, Biomed. Mass Spectrom., 1975, 2, 2-8). 

Half-life. Plasma half-life, about 2 hours, ritalinic acid about 8 hours. 

A novel metabolite of methylphenidate, ethylphenidate, has recently been detected in human blood and liver samples obtained from two suicide victims who had taken a large dose of methylphenidate and ethanol (49). The concentrations of ethylphenidate were small relative to those of methylphenidate and ritalinic acid. Nevertheless, given the frequent occurrence of methylphenidate and ethanol co-ingestion, the detection of ethylphenidate warrants further studies on the extent of its formation, as well as any associated toxicity associated with normal doses. A transesterification reaction, analogous to that known to produce cocaethylene after cocaine and ethanol co-ingestion (50), has been described with methylphenidate (51). 

Methylphenidate (MPH, Ritalin ) is a central nervous system stimulant that is used for the treatment of attention deficit disorders, with and without hyperactivity, and narcolepsy. MPH has two chiral centres and is marketed as a racemic mixture. It is known that d-threo-MP is pharmacologically more active than l-threo-MPH. The drag is rapidly metabohzed in humans to the inactive ritalinic acid. High-throughput analysis with chiral selectivity is demanded for the bioanalysis of MPH and its major metabolite. 

In order to study the effects of chronic administration on the cognitive function of children by means of nonhuman primates, a method was developed for the determination of MPH plasma levels under chronic and acute dosing conditions [60]. MPH and ritalinic acid were isolated from plasma in SPE on Oasis HLB. LC was performed using a 15Qx2-mm-lD Cig column (3 pm) and 20% acetonitrile in 0.1% aqueous formic acid at a flow-rate of 0.2 ml/min. Positive-ion ESI-MS was performed in SIM mode on a single-quadrapole system. [Z)3]-MPH was used as ILIS. The LOQ was 0.25 ng/ml in monkey plasma. 

Mixed-mode SPE procedures using Oasis-HLB materials (Ch. 1.5.3) were described above for the determination of risperidone and its hydroxylated metabolites [14], and of MPH and its metabolite ritalinic acid [60]. The mixed-mode materials are also available in 96-well plate format, as described above for the analysis of rosuvastatin in human plasma [54] and in the method development for metabolic incubation studies with 27 candidate drags [92]. 

D.R. Doerge, C.M. Fogle, M.G. Paule, M. McCuUagh, S. Bajic, Analysis of methylphenidate and its metabolite ritalinic acid in monkey plasma by LC-ESI-ALS,... 

Methylphenidate is an ester, and the methyl ester is rapidly cleaved. The ester hydrolysis product, called ritalinic acid, comprises about 80% of the urinary metabolites after an orally administered dose (67). The lability of the ester function is probably the major factor limiting the oral bioavailability of... 

Methylphenidate is rapidly metabolized to ritalinic acid (Figure 34-21), which accounts for 60% to 89% of a dose... 

Doerge, D.R. Fogle, C.M. Paule, M.G. McCullagh, M. Bajic, S. Analysis of Methylphenidate and its Metabolite Ritalinic Acid in Monkey Plasma by Liquid Chromatography/Electrospray Ionization Mass Spectrometry, Rapid Commun. Mass Spectrom. 14, 610-623 (2000). 

Methylphenidate is readily absorbed after oral administration and reaches peak concentrations in plasma in about 2 hours. The drug is a racemate its more potent (+) enantiomer has a half-Ufe of about 6 hours, and the less potent (-) enantiomer has a half-life of about 4 hours. Concentrations in the brain exceed those in plasma. The main urinary metabolite is a deesterifled product, ritalinic acid, which accounts for 80% of the dose. The use of methylphenidate is contraindicated in patients with glaucoma. 

It is rapidly absorbed from the GI-tract. Approximately, 80% of an orally administered dose gets metabolized to the corresponding ritalinic acid and subsequently excreted in the urine. In fact, its actions, like cocaine, seem to be regulated by blockade of catecholamine reuptake instead by the release of catecholamines as usually takes place with the amphetamines in general. 

Methylphenidate has a short half-life mainly due to conversion to the inactive metabolite ritalinic acid, but co-administration of alcohol and methylphenidate has been reported to result in production of a minor me-... 

A Sensitive Gas Chromatographic Method for the Determination of Methylphenidate (Ritalin) and Its Major Metabolite a-Phenyl-2-piperidine Acetic Acid (Ritalinic Acid) in Human Plasma Using Nitrogen-Phosphorus Detector Commun. Psychopharmacol. 2(3) 203-208 (1978) CA 90 15976e... 

A Chemical Ionization Selected Ion Monitoring Assay for Methylphenidate and Ritalinic Acid... 

Gas-Liquid Chromatographic Procedure for Measurement of Methylphen-idate Hydrochloride and Its Metabolite, Ritalinic Acid, in Urine... 

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