A Comparative Analysis of Pharmacokinetic Variations


Methylphenidate hydrochloride (MPH) (C14H19NO2 – HCl) is a psychomotor stimulant that targets the central nervous system (CNS) to aid in the treatment of attention-deficit hyperactivity disorder (ADHD), as well as narcolepsy, primarily in children and adolescents. This is because of the pharmacodynamic mechanisms of MPH, which include its ability to inhibit monoamine oxidase activity, and reuptake of noradrenaline and dopamine, as well as its ability 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 less frequent dosing times per day, unlike immediate-release (IR) tablets, so that those with a strict timetable are able to work around dosing times with increased ease. This research article aims to compare the different formulations in terms of how it has been developed, and how this relates to its pharmacokinetic mechanisms.

While primary sources have been sourced and interpreted for the purpose of this research article, it is important to note that not every study has necessarily taken into account of the fact that the study of psychostimulants require multiple variables, such as the subject’s sex, and age of initial drug exposure (Schmeichel and Berridge, 2013).

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Development of Methylphenidate Tablets To Allow For Extended Release Dosing Mechanism

While the XR tablet retains the same active ingredient, MPH, it will have undergone changes to allow for its ability to release the stimulant within the body over a period of time. This mechanism is used constantly during pharmacological drug development when developing XR formulations.

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One such example of XR MPH is known as HLD200, where three crossover studies have been conducted to evaluate the pharmacokinetic properties of XR MPH tablets (Liu et al., 2019). It contains an outer coating that reacts to the conditions within the GI tract and as it is being absorbed, where the coating slowly erodes and allowing for the stimulant to be metabolized. In that, it is made of hydrophobic and insoluble polymers that aid in delaying the process of wetting the outer coating and in turn, dissolution. As the coating is slowly wetted, GI fluids are able to react with a pH-sensitive polymer, which is only soluble when the pH level is above 7 (Liu et al., 2019). This allows for the coating to erode and hence 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 form 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 often ingested orally when doses are administered, where it travels through the digestive tract and absorbed mainly within the gastrointestinal (GI) tract, especially the intestines, at a rapid rate (Wada et al., 2011). Furthermore, MPH can also be absorbed via 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 is found after 7-10 hours. MPH possesses a relatively short half-life of 2-3 hours as it is being absorbed, meaning that patients will have to take several doses throughout the day. The drug is then distributed to the CNS as well as other tissue, with 57% of the drug distributed into the plasma and 43% into the erythrocytes, as shown by a randomized controlled trial to compare the bioavailability as well as absorption between MPH formulations (Stage et al., 2017). The steady-state volume of distribution is further calculated to be at around 2L/kg. Biotransformation of MPH then occurs as it hydrolyzes into the metabolite, ritalinic acid (RA) through immobilized and free enzymes. RA is inactive and is also known as the primary metabolite of MPH. In an animal study using Wistar male rats to observe the pharmacokinetics of MPH and RA, it is found that 480 minutes after the initial dosing of MPH, RA concentration was seen to be higher than MPH by 8 times (Wada et al., 2011). Although it must be acknowledged that animal studies regarding medication such as MPH may not be accurate, as they tend to be administered through injection, which could cause a different response than if it were taken orally, such as an increase in peak concentrations in the pharmacokinetic profile, not found in humans (Childress et al., 2018).

MPH is catalyzed by the carboxylesterase 1 (CES1) enzyme into RA in its main pathway, whereas less abundant metabolites such as the p-hydroxy-metabolites, oxo-metabolites, and conjugated metabolites are formed within minor pathways (Kobakhidze et al., 2018). These minor pathways include that of aromatic hydroxylation, microsomal oxidation, as well as conjugation, respectively. In a clinical study of CES1 in relation to MPH, CES1 143E alleles are seen to possess a significant impact on MPH metabolism unlike CES1A1c, which shown no effect (Jang et al., 2019). MPH is excreted primarily as RA, with only 1% of MPH is excreted without undergoing biotransformation (Kharas et al., 2019). The drug is also able to be excreted through hair, and this has been useful in the past when identifying those who abuse the stimulant, as determined mass-spectrometry analysis of the subject’s hair, as shown through a study in the analysis of hair to determine MPH intake (Thanos et al., 2015).

With a mechanism that allows for XR dosing, this changes the pharmacokinetic properties of the formulation. One major difference is that the absorption, distribution and metabolism rate of the stimulant is constant and occurs at a steady pace, as opposed to the IR formulation allowing for MPH to be absorbed and metabolized rapidly. Metabolism pathways still remain the same for both the XR and IR formulation, however. Aside from the fact that XR MPH will be excreted in parts as the dose is being gradually administered, XR MPH is also excreted in the same 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 effects of methylphenidate and MDMA administered alone or in combination. Int J Neuropsychopharmaco 17(3): 371-81.
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  5. Kobakhidze A, Elisashvili V, Corvini PF, M (2018). Biotransformation of ritalinic acid by laccase in the presence of mediator TEMPO. N Biotechnol 43: 44-52.
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  7. Schmeichel BE, Berridge CW (2013). Neurocircuitry Underlying the Preferential Sensitivity of Prefrontal Catecholamines to Low-Dose Psychostimulants. Neuropsychopharmacology 38(6): 1078-84.
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  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 in the rat and effects on behavior. 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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A Comparative Analysis of Pharmacokinetic Variations. (2019, Dec 02). Retrieved from https://studymoose.com/a-comparative-analysis-of-pharmacokinetic-variations-essay

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