A Comparative Analysis of Pharmacokinetic Variations


Methylphenidate hydrochloride (MPH) (C14H19NO2 – HCl) is a psychomotor stimulant that targets the central nervous system (CNS) to help in the remedy of attention-deficit hyperactivity dysfunction (ADHD), in addition to narcolepsy, primarily in children and adolescents. This is due to the pharmacodynamic mechanisms of MPH, which embrace its capacity to inhibit monoamine oxidase exercise, and reuptake of noradrenaline and dopamine, as well as its capacity to facilitate the release of such neurotransmitters into the synaptic cleft (Hysek et al.

, 2014). Extended-release (XR) tablets of MPH have been developed that require much less frequent dosing occasions per day, unlike immediate-release (IR) tablets, in order that these with a strict timetable are able to work around dosing occasions with increased ease. This analysis article goals to match the different formulations when it comes to the means it has been developed, and how this relates to its pharmacokinetic mechanisms.

While main sources have been sourced and interpreted for the aim of this research article, it is essential to notice that not every examine has essentially taken under consideration of the reality that the examine of psychostimulants require multiple variables, such because the subject’s sex, and age of initial drug publicity (Schmeichel and Berridge, 2013).

Development of Methylphenidate Tablets To Allow For Extended Release Dosing Mechanism

While the XR pill retains the identical active ingredient, MPH, it will have undergone modifications to permit for its capacity to release the stimulant throughout the body over a period of time. This mechanism is used constantly during pharmacological drug development when creating XR formulations.

One such example of XR MPH is called HLD200, where three crossover studies have been carried out to gauge the pharmacokinetic properties of XR MPH tablets (Liu et al., 2019). It contains an outer coating that reacts to the conditions throughout the GI tract and as it’s being absorbed, where the coating slowly erodes and allowing for the stimulant to be metabolized. In that, it’s made of hydrophobic and insoluble polymers that assist in delaying the method of wetting the outer coating and in turn, dissolution. As the coating is slowly wetted, GI fluids are in a place to react with a pH-sensitive polymer, which is only soluble when the pH degree is above 7 (Liu et al., 2019). This permits for the coating to erode and therefore reveals the layer containing the stimulant. Hence, in order to regulate the dissolution and permeability of MPH, the stimulant contains hydrophobic and soluble polymers, which had been developed with MPH to kind the XR MPH formulation (Liu et al., 2019).

The Pharmacokinetics of Extended-Release Formulation

In Contrast to that of Immediate Release Methylphenidate Tablets MPH is commonly ingested orally when doses are administered, the place it travels through the digestive tract and absorbed mainly within the gastrointestinal (GI) tract, especially the intestines, at a speedy fee (Wada et al., 2011). Furthermore, MPH may additionally be absorbed by way of the plasma found in blood, and it is observed that maximal plasma levels of the IR MPH are found 1-3 hours post-dosing, whereas, for XR MPH, it’s found after 7-10 hours. MPH possesses a comparatively short half-life of 2-3 hours as it’s being absorbed, meaning that patients must take several doses throughout the day. The drug is then distributed to the CNS in addition to different tissue, with 57% of the drug distributed into the plasma and 43% into the erythrocytes, as proven by a randomized managed trial to compare the bioavailability as properly as absorption between MPH formulations (Stage et al., 2017). The steady-state quantity of distribution is additional calculated to be at round 2L/kg. Biotransformation of MPH then happens because it hydrolyzes into the metabolite, ritalinic acid (RA) by way of immobilized and free enzymes. RA is inactive and is also called the primary metabolite of MPH. In an animal study using Wistar male rats to watch the pharmacokinetics of MPH and RA, it’s found that 480 minutes after the preliminary dosing of MPH, RA concentration was seen to be greater than MPH by eight instances (Wada et al., 2011). Although it should be acknowledged that animal studies concerning medication corresponding to MPH is in all probability not accurate, as they are typically administered by way of injection, which may trigger a unique response than if it had been taken orally, similar to an increase in peak concentrations within the pharmacokinetic profile, not present in humans (Childress et al., 2018).

MPH is catalyzed by the carboxylesterase 1 (CES1) enzyme into RA in its main pathway, whereas much less ample metabolites such as the p-hydroxy-metabolites, oxo-metabolites, and conjugated metabolites are shaped inside minor pathways (Kobakhidze et al., 2018). These minor pathways embody that of fragrant hydroxylation, microsomal oxidation, in addition to conjugation, respectively. In a clinical research of CES1 in relation to MPH, CES1 143E alleles are seen to own a major impact on MPH metabolism not like CES1A1c, which proven no effect (Jang et al., 2019). MPH is excreted primarily as RA, with solely 1% of MPH is excreted without present process biotransformation (Kharas et al., 2019). The drug can also be capable of be excreted by way of hair, and this has been useful in the past when figuring out those who abuse the stimulant, as determined mass-spectrometry evaluation of the subject’s hair, as proven via a examine within the evaluation of hair to find out MPH consumption (Thanos et al., 2015).

With a mechanism that enables for XR dosing, this adjustments the pharmacokinetic properties of the formulation. One main distinction is that the absorption, distribution and metabolism fee of the stimulant is fixed and occurs at a steady pace, versus the IR formulation permitting for MPH to be absorbed and metabolized quickly. Metabolism pathways still remain the identical for both the XR and IR formulation, nevertheless. Aside from the fact that XR MPH will be excreted in components as the dose is being steadily administered, XR MPH can also be excreted in the identical manner as IR MPH.


  1. Childress A, Stark JG, McMahen R, Engelking D, Sikes C (2018). A Comparison of the Pharmacokinetics of Methylphenidate Extended-Release Orally Disintegrating Tablets With a Reference Extended-Release Formulation of Methylphenidate in Healthy Adults. Clin Pharmacol Drug Dev 7(2): 151-159.
  2. Hysek CM, Simmler LD, Schillinger N, Meyer N, Schmid Y, Donzelli M, Grouzmann E, Liechti ME (2014). Pharmacokinetic and pharmacodynamic results of methylphenidate and MDMA administered alone or together. Int J Neuropsychopharmaco 17(3): 371-81.
  3. Jang M, Kim J, Shin I, Kang S, Choi H, Yang W (2019). Simultaneous dedication of methylphenidate and ritalinic acid in hair using LC-MS/MS. Forensic Sci Int 294: 183-188.
  4. Kharas N, Yang P, Castro-Alvarado D, Rose K, Dafny N (2019). Exposure to methylphenidate in adolescence and maturity modulates cross-sensitization to amphetamine in maturity in three genetically variant female rat strains. Behav Brain Res 362: 36-45.
  5. Kobakhidze A, Elisashvili V, Corvini PF, M (2018). Biotransformation of ritalinic acid by laccase in the presence of mediator TEMPO. N Biotechnol forty three: 44-52.
  6. Liu T, Gobburu JVS, Po MD, McLean A, DeSousa NJ, Sallee FR, Incledon B (2019). Pharmacokinetics of HLD200, a Delayed-Release and Extended-Release Methylphenidate: Evaluation of Dose Proportionality, Food Effect, Multiple-Dose Modeling, and Comparative Bioavailability with Immediate-Release Methylphenidate in Healthy Adults. J Child Adolesc Psychopharmacol 29(3): 181-191.
  7. Schmeichel BE, Berridge CW (2013). Neurocircuitry Underlying the Preferential Sensitivity of Prefrontal Catecholamines to Low-Dose Psychostimulants. Neuropsychopharmacology 38(6): 1078-84.
  8. Stage C, J?rgens G, Guski LS, Thomsen R, Bjerre D, Ferrero-Miliani L, Lyauk YK, Rasmussen HB, Dalhoff K; INDICES Consortium (2017). The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish topics. Br J Clin Pharmacol 83(7): 1506-1514.
  9. Thanos PK, Robison LS, Steier J, Hwang YF, Cooper T, Swanson JM, Komatsu DE, Hadjiargyrou M, Volkow ND (2015). A pharmacokinetic model of oral methylphenidate within the rat and results on habits. Pharmacol Biochem Behav 131: 143-53.
  10. Wada M, Abe K, Ikeda R, Kikura-Hanajiri R, Kuroda N, Nakashima K (2011). HPLC determination of methylphenidate and its metabolite, ritalinic acid, by high-performance liquid chromatography with peroxyoxalate chemiluminescence detection. Anal Bioanal Chem 400(2): 387-93.
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