PharmGKB summary

Methylphenidate for attention-deficit/hyperactivity disorder in adults: a narrative review

“…The process described here is enantio-selective, which implies significantly higher plasma concentration and longer T ½ of d -MPH in comparison to l -MPH (because CES1A1 has six-fold higher preference for l -MPH versus d -MPH) (Dinis-Oliveira 2017 ). Notably, CES1A1 is closely related to CES2; however, MPH is metabolized by CES1 only (Stevens et al 2019 ). In studies on various oral formulations of MPH, it was shown that AUC 0-inf for the l enantiomer is equal to just 1–15% of the AUC 0-inf value for d -MPH (Patrick et al 2005 ).…”

“…As a consequence of microsomal oxidation, 6-oxo-methylphenidate (another inactive metabolite of MPH) may be formed, which is further converted to 6-oxo-ritalinic acid via de-esterification (Stevens et al 2019 ).…”

“…After oral administration, 50% of a dose of methylphenidate is excreted in the urine within 8 h and 90% by 48 h post-administration (Wolraich and Doffing 2004 ). About 1–3% of the dose administered orally is excreted in feces, and less than 1–2% is eliminated unchanged in urine (Childress et al 2019 ; Stevens et al 2019 ).…”

“…In vitro studies suggest that MPH is characterized by particularly high affinity (independent of the model used) for DAT (solute carrier family 6A member 3 — SLC6A3), slightly lower to NAT (solute carrier family 6A member 2 — SLC6A2), with virtually no effect on the activity of the serotonin transporter (SERT; also known as solute carrier family 6A member 4 — SLC6A4) (Markowitz et al 2006 ; Markowitz and Patrick 2008 ; Williard et al 2007 ). It was reported that MPH has almost 1300 times greater affinity for NAT, and about 2200 times greater affinity for DAT, in comparison to SERT (Stevens et al 2019 ). Noteworthy, there is considerable variation in the strength of MPH binding to both DAT and NAT, depending on the enantiomer used (Markowitz and Patrick 2008 ).…”

“…Studies on the effects of MPH as a DAT blocker are quite hard to conduct, because of the heterogeneity of dopaminergic receptors. Although MPH has not been shown to have any affinity for dopamine receptors, it is likely to influence their function as well (Stevens et al 2019 ). It is suggested that inhibition of dopamine reuptake by MPH reduces dopaminergic activity through increased stimulation of presynaptic inhibitory autoreceptors.…”