Chemical formula: C₁₄H₁₉NO₂ Molecular mass: 233.306 g/mol PubChem compound: 4158
Methylphenidate is a CNS stimulant (psychostimulant) with more pronounced effects on central than on motor activities. Methylphenidate exists in four stereoisomers, with the threo-form being the pharmacodynamically active configuration. The D-isomer is pharmacologically more active than the L-isomer.
The mechanism of action in humans is not fully understood; however, it is thought that the effect is due to inhibition of dopamine reuptake in the striatum without triggering a release of dopamine. In particular, methylphenidate binds to dopamine transporters (DAT) and norepinephrine transporters (NET) that are usually responsible for the reuptake of these neurotransmitters from the synaptic cleft. It blocks these transporters causing an increase in synaptic levels of dopamine (DA) and norepinephrine (NE) and an increase in extracellular DA in the striatum, nucleus accumbens, and prefrontal cortex. Both the DA receptor subtypes 1 (D1) and 2 (D2), as well as the μ-opioid receptor are important for the rewarding and therapeutic effects of MPH. Nevertheless, the mechanism by which methylphenidate produces the cognitive and behavioural effects has not been clearly established.
The central stimulating effect is expressed, among other things, in an increase in the ability to concentrate, readiness to perform and make decisions, psychophysical activity as well as in suppression of tiredness and physical fatigue. The indirect sympathomimetic effect of methylphenidate in humans can also lead to an increase in blood pressure, acceleration of the pulse rate and a reduction in the tone of the bronchial muscles. These effects are usually not very pronounced. Methylphenidate can reduce appetite and, at high doses, lead to an increase in body temperature. Behavioural stereotypies can also be triggered at high doses or after prolonged use.
Population PK models were developed for methylphenidate for extended- and the immediate-release formulations. Similarity across extended-release treatment with respect to the PD outcome was shown. Modelling and simulation assessed the impact of differences in PK profile shape between extended- and the immediate-release formulations on efficacy, represented as SKAMP score in the target population of children with ADHD. The results of the analysis supported the claimed clinical noninferiority in the 12 hours post dose time frame for the proposed extended-release formulations compared to the immediate-release formulation.
The active substance methylphenidate hydrochloride is rapidly and almost completely absorbed from the immediate-release tablets. Owing to extensive first-pass metabolism the absolute bioavailability was 22±8% for the d-enantiomer and 5±3% for the l-enantiomer. Peak plasma concentrations (Cmax) of approximately 11 ng/ml are attained, on average, 1-2 hours after administration of 0.30 mg/kg. The area under the concentration-time curve (AUC) and the Cmax, are proportional to the dose.
Following a single oral dose of 40 mg Methylphenidate hydrochloride under fasting conditions, plasma methylphenidate reached maximal concentration (Cmax) at a median time of 5 hours after dosing. Methylphenidate Cmax and exposure (area under the curve, AUC) were approximately 12 ng/ml and 112 ng×h/ml, respectively.
Following a single oral dose of 40 mg under fed conditions, Methylphenidate hydrochloride exhibited Cmax and AUC values of approximately 15 ng/ml and 133 ng×h/ml, respectively. Both AUC and Cmax were also proportional to dose between the dose range of 20-40 mg after a single dose of methylphenidate in healthy subjects under fed conditions.
There is considerable inter- and intra-individual variation in plasma concentration.
High-fat meal had no effect on the time to peak concentration, and increased Cmax and systemic exposure (AUC0-∞) of methylphenidate by about 20% and 4%, respectively, after a single dose administration of 40 mg Methylphenidate hydrochloride.
In the blood, methylphenidate and its metabolites are distributed between plasma (57%) and erythrocytes (43%). Binding of methylphenidate and its metabolites to plasma proteins is low at 10-33%. The volume of distribution is 2.65±1.11 L/kg for d-methylphenidate and 1.80±0.91 L/kg for l-methylphenidate.
Methylphenidate is rapidly and almost completely metabolised by the carboxylesterase CES1A1. It is primarily broken down into ritalinic acid. Peak plasma levels of ritalinic acid are reached approximately 2 hours after dosing with an immediate release formulation and are 30 to 50 times higher than those of methylphenidate. The half-life of ritalinic acid is approximately twice that of methylphenidate and the systemic clearance is 0.17 l/h/kg. This allows accumulation in patients with renal insufficiency. Since ritalinic acid has little or no pharmacodynamic activity, this plays a minor role therapeutically. Only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable.
Therapeutic activity seems to be mainly limited to methylphenidate.
Plasma methylphenidate concentrations decline monophasically following oral administration of Methylphenidate hydrochloride. The mean plasma terminal elimination half-life of methylphenidate was about 5. hours in healthy volunteers following a single 40 mg dose administration. Only small amounts (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60-86%), presumably independent of pH.
There appear to be no differences in the pharmacokinetics of methylphenidate between children with hyperkinetic disorders/ADHD and healthy adult subjects. Elimination data from patients with normal renal function suggest that renal elimination of unmetabolised methylphenidate is hardly affected by impaired renal function. Renal excretion of the main metabolite ritalinic acid may be reduced.
In lifetime rat and mouse carcinogenicity studies, increased numbers of malignant liver tumours were noted in male mice only. The significance of this finding to humans is unknown.
Methylphenidate did not affect reproductive performance or fertility at low multiples of the clinical dose.
Methylphenidate is not considered to be teratogenic in rats and rabbits. Foetal toxicity (i.e., total litter loss) and maternal toxicity was noted in rats at maternally toxic doses.
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