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Dermal and Transdermal Drug Delivery Systems
Published in Tapash K. Ghosh, Dermal Drug Delivery, 2020
Kenneth A. Walters, Majella E. Lane
Methylphenidate (α-phenyl-2-piperidineacetic acid methyl ester, Figure 1.2) is a mild central nervous system stimulant used in the treatment of attention-deficit disorder (ADD) and attention-deficit hyperactivity disorder (ADHD) in children and adults (Ghuman et al., 2008; Wilens et al., 2011). The active agent exists both in a free base form and in an ionized form (most commonly as the hydrochloride). Methylphenidate hydrochloride and methylphenidate base have two stereogenic carbon atoms, which give rise to four stereoisomers. The four stereoisomers consist of two pairs of enantiomers, d- and l-threo-methylphenidate and d- and l-erythro-methylphenidate (Patrick et al., 1987). The most active stereoisomer is d-threo-methylphenidate and it is responsible for the therapeutic action of the drug. Methylphenidate is metabolized primarily by deesterification to ritalinic acid, which is pharmacologically inactive.
Detection and Identification of Amphetamine and Related Stimulants
Published in John Caldwell, S. Joseph Mulé, Amphetamines and Related Stimulants: Chemical, Biological, Clinical, and Sociological Aspects, 2019
The majority of systems described in the literature employ flame ionization detectors (FID), but additional sensitivity has been obtained for the amphetamines by the application of electron capture detectors (ECD) to appropriate derivatives,2, 13 and the application of nitrogen/phosphorus detectors (NPD).2, 8 Derivatization techniques have also been used to supply additional retention data and functional group information to improve the specificity of GLC.2,3,11,12 Combined gas chromatography-mass spectrometry provides the ultimate in GLC systems. This technique is able to provide definitive, quantitative data with very high sensitivities. An example of its use for amphetamine-related drugs is the identification and quantification in serum of methylphenidate and its major metabolite, ritalinic acid.14
Clinical Aspects Related to Methylphenidate-Based NPS
Published in Ornella Corazza, Andres Roman-Urrestarazu, Handbook of Novel Psychoactive Substances, 2018
Dino Lüthi, Matthias E. Liechti
The pharmacokinetics of newly emerged NPSs has been relatively unexplored, so the pharmacokinetics of MPH will be discussed in this section. After oral administration, MPH is rapidly and completely absorbed (Kimko, Cross, & Abernethy, 1999), and peak blood concentrations are reached 1–2 hours after administration (Faraj et al., 1974; Gualtieri et al., 1982; Srinivas, Hubbard, & Midha, 1990; Wargin et al., 1983). When MPH is injected, peak drug concentrations in the brain are reached 4–10 minutes after the injection and maintained for 15–20 minutes (Volkow et al., 1995). The D-enantiomer of MPH was shown to be more active than the L-enantiomer (Patrick, Caldwell, Ferris, & Breese, 1987). Methylphenidate is stereoselectively metabolized, resulting in higher plasma D-MPH concentrations (Aoyama, Kotaki, Honda, & Nakagawa, 1990; Srinivas et al., 1990). The main metabolic pathway includes the de-esterification of MPH to ritalinic acid by a hepatic esterase to the pharmacologically inactive metabolite ritalinic acid (Faraj et al., 1974; Patrick, Kilts, & Breese, 1981; Wargin et al., 1983). In a pharmacokinetics study, ~70–75% of a dose of D-MPH and L-MPH was recovered as D-ritalinic acid and L-ritalinic acid, respectively (Aoyama et al., 1990). In a controlled clinical study of healthy volunteers, the average half-life of MPH was 2.8 hours (Hysek et al., 2014). The acute subjective and cardiostimulant effects of oral MPH (60 mg) reflect the plasma concentration-time profile of MPH relatively well and last four to six hours (Dolder et al., 2017; Hysek et al., 2014).
Characterisation of seven medications approved for attention-deficit/hyperactivity disorder using in vitro models of hepatic metabolism
Published in Xenobiotica, 2022
Rebecca Law, David Lewis, Daniel Hain, Rachel Daut, Melissa P. DelBello, Jean A. Frazier, Jeffrey H. Newcorn, Erika Nurmi, Elizabeth S. Cogan, Susanne Wagner, Holly Johnson, Jerry Lanchbury
After administration of MPH to cPHHs, dMPH and L-MPH were undetectable after 24 h and exhibited half-lives of 217 and 72.9 min, respectively (Table 1). After dMPH administration, dMPH had a similar half-life of 289 min. Also, greater than 500 pmol of ritalinic acid was detected after MPH and dMPH administration (Figure 2(E,F)). However, not all of the substrate loss could be attributed to the presence of cPHHs, as substantial non-enzymatic degradation of MPH and dMPH was observed (Supplemental Table 1). Coupled with the fact that non-enzymatic degradation led to substantial formation of ritalinic acid (Supplemental Figure 1), the fraction enzymatically-metabolised via these pathways could not be estimated. P-OH-MPH and oxo-MPH also formed only in the presence of cPHHs and were detected using their area ratios (data not shown). Ethylphenidate was not detected in any condition.
Is genetic variability in carboxylesterase-1 and carboxylesterase-2 drug metabolism an important component of personalized medicine?
Published in Xenobiotica, 2020
S. Casey Laizure, Robert B Parker
Methylphenidate is a central nervous system stimulant used to treat attention deficit disorder. The active drug is methylphenidate, which is metabolized to the inactive ritalinic acid by CES1-catalyzed hydrolysis. A reduction in CES1 enzyme activity in carriers of the c.428GA allele would be expected to reduce the clearance of methylphenidate altering its disposition. In a study conducted in 22 Danish, Caucasian normal volunteers taking a single 10 mg dose of methylphenidate, carriers of the c.428GA allele (n = 6) had a dex-methylphenidate AUC and Cmax of 53.3 ng/mlxh and 9.1 ng/mL compared to 21.4 ng/mlxh and 5.0 ng/mL in 428GG carriers (n = 16), respectively. This represents a 150% increase in the AUC and 82% increase in the Cmax in carriers of the variant allele. The large increase in the Cmax suggests a decrease in first-pass metabolism of methylphenidate increasing its bioavailability. This would be consistent with the finding in children who were carriers of the 428GA allele showing a lower dose of methylphenidate was required to achieve a therapeutic response (0.410 mg/kg versus 0.572 mg/kg, p < .022) (Nemoda et al., 2009).
The interpretation of hair analysis for drugs and drug metabolites
Published in Clinical Toxicology, 2018
Eva Cuypers, Robert J. Flanagan
Hair analysis has been reported as showing chronic administration of sertraline and quetiapine, but not methylphenidate, to a 4-year-old previously healthy boy who was admitted after suspected accidental ingestion of methylphenidate, sertraline and quetiapine prescribed to his 8-year-old brother [80]. Sertraline and quetiapine and their metabolites were identified in plasma and in urine and the child recovered uneventfully. Quetiapine was found in the first four of six consecutive 2 cm hair segments (mean concentration 1.00 ± 0.94 ng/mg hair) and sertraline and norsertraline were found in all segments (mean concentrations 2.65 ± 0.94 ng/mg and 1.50 ± 0.94 ng/mg hair, respectively. The highest concentrations were found in the segments nearest the root. Methylphenidate and ritalinic acid were not detected in any segment. The hair segments were washed with dichloromethane and with methanol prior to the analysis. Given that there was a large systemic exposure to quetiapine and sertraline, the assertion that the hair analysis showed chronic drug administration to the child would seem speculative at best.