Pharmacokinetics and Metabolism of Methylphenidate

August 15, 2015 at 02:12 PM | categories: genetics

Contents

1 Pharmacokinetics of MPH
 1.1 Sustained-release preparations of MPH
 1.2 Placebo effects of MPH

1 Pharmacokinetics of Methylphenidate

Age at the time of drug treatment and pharmacokinetic differences in absorption, distribution and metabolism could influence both the acute and chronic effects of psychostimulants [28]. For a 10 mg dose in a 30 kg child, the maximum serum concentration occurs about 1.5 to 2 hours afterward and leads to concentrations of approximately 10 ng/mL in plasma after administration, dropping by 50 % about 2 hours later [4]. However, the optimal therapeutic dose varies considerably across individuals [9]. There is great variability among subjects and among dosing regimens in the rate of absorption of methylphenidate (MPH) and the rate of decay of MPH from plasma. This led to a 3.5-fold difference in blood levels between subjects taking the same dose in the most extreme case [21]. The therapeutic effects parallel the serum concentration of immediate-release MPH, with a maximum reduction in attention-deficit/hyperactivity disorder (ADHD) symptoms about 1.5 to 2 hours after dosing followed by a decline that is sufficient to require another dose about 4 hours after the first to reestablish full efficacy [23].

Oral MPH in normal adults has a half-life of about 2.1 h, the time to peak plasma concentration is about 2.2 h. Ritalinic acid (major metabolite) reaches peak plasma concentration at approximately the same time as MPH except that levels were several-fold those of MPH [27]. Oral MPH in ADHD children isn’t too different: half-life 2.4 h; time to peak 1.5 h [27].

MPH undergoes extensive and stereospecific presystemic metabolism [1] to form predominantly the inactive hydrolysis product, ritalinic acid, resulting in a low absolute oral bioavailability. The bioavailability of oral MPH measured in rat is 0.19, in monkey 0.22, with considerable intersubject variability: ranging from 0.08 to 0.44 in both species [27]. Animal studies have suggested that MPH is subject to substantial first-pass and presystemic metabolism, the primary action of presystemic metabolism is deesterification in the gut and/or intestinal wall [1, 27]. Interestingly, the rate and extent of d-MPH absorption were similar when administered with or without food [22]. MPH is metabolized extensively in the rat; less than 1 % unchanged MPH was found in the 48 h urine [7].

Intravenous administration of 1 mg/kg of MPH in rats shows rapid accumulation of MPH in the brain, the peak brain concentration within the first minute after injection [13]. Transfer of MPH from plasma to tissues is rapid and distribution is extensive [7]. During the first 30 min after MPH administration, there was an average of 8-fold greater MPH concentration in brain vs. plasma [13]. Peak serum and brain concentrations after oral administration of 1 mg/kg of MPH occurred at 10 min after dosing. At 45 min after dosing, the brain/serum ratios were approximately equal for both i.v. and oral routes of administration [13]. The half-life of MPH in the rat is 24.8 min [7]. MPH is ionized at physiological pH to a lesser extent than dextroamphetamine (D-AMPH) and is considerably more lipid soluble, which will induce quicker rise times to the brain [7].

After oral administration of [11C]d-threo-MPH, the radiolabeled d-MPH was distributed stereoselectively in the rat brain, especially in the striatum. Further, it was shown that the d-isomer binds specifically to dopamine (DA) uptake sites in the striatum [2]. [11C]l-threo-MPH had an homogeneous distribution throughout the brain (after i.v. administration) [26]. The rate of uptake in the brain for the two enantiomers was eqivalent but the clearance was significantly slower for [11C]d-threo-MPH than for the l-isomer. The therapeutic and safety profile of d-MPH is similar to that of racemic d,l-MPH [15]. However, l-MPH offers anxiolytic and antipsychotic activity, serves as an antidote for stimulant overdose [3], reduces cocaine induced locomotor sensitization [6], and pretreatment with l-MPH attenuates the motor activity response to d-MPH [5].

The median effective dose (ED50) for dopamine transporter (DAT) blockade was calculated to be 0.25 mg/kg oral MPH [24] and 0.075 mg/kg i.v. MPH [25]; the half maximal inhibitory concentration (IC50) of MPH at DAT: 84 nm [8]. The ED50 estimate for global norepinephrine transporter (NET) was 0.14 mg/kg ± 0.02 mg/kg MPH, although the local ED50 did vary by brain region [10]; the IC50 of MPH at NET: 510 nm [8] If occupancy = ---dose-- dose+ED50 [10], then the average efficacious maintenance doses of MPH used in children and adults occupy 70 % to 80 % of NET but only 60 % to 70 % of DAT, based on the estimated ED50 value of 0.14 mg/kg for NET and 0.25 mg/kg for DAT [24]. Interestingly, NET has greater affinity for DA than for norepinephrine (NE) [12], and whether DAT or NET is the predominant protein clearing DA depends on the abundance of the two transporters in a given region [11].

1.1 Sustained-release preparations of MPH

In recent years, new drug delivery methods have been developed to enhance the duration of action [21]. Through these efforts to develop effective long-acting MPH preparations, valuable new information has become available on the relationship between dosing regimens, blood levels, and therapeutic response. Efficacy of MPH declined in an administration regimen designed to provide consistent stable blood levels, presumably due to acute tolerance due to an adaptation response at the synaptic level in response to blockade of the DAT [18, 20]. This confirmed and extended findings of rapid tolerance previously observed by Srinivas et al. [16] in an acute administration paradigm. This lead to the discovery that there are two alterative strategies for providing sustained efficacy: Pulsatile delivery or escalating blood levels [17]. With pulsatile delivery, there is a drop in blood levels that enables the system to retain or regain sensitivity. With escalating delivery, the increasing blood levels presumably help to overcome emerging tolerance and waning sensitivity [19].

1.2 Placebo effects of MPH

Subjects receiving placebo showed no significant degree of benefit and on average were slightly worse following placebo administration than when they first arrived at the laboratory in an unmedicated state [21]. ADHD does not appear to be a placebo-responsive disorder when evaluated using objective measures. Instead, after placebo administration, a clear pattern of deterioration across the day emerges, in contrast to the pattern of improvement with MPH [18]. Improvement of ADHD children on placebo in studies using observer ratings is probably due in large part to a halo effect, in which teachers or parents score children differently if they believe that they have been medicated [21]. Also, when MPH is given therapeutically and produces large improvements in the classroom, children with ADHD do not attribute this ‘success’ to the drug [14]. This indicates that expectancy does not play a prominent role in MPH’s therapeutic effects.

Acronyms

ADHD
attention-deficit/hyperactivity disorder
D-AMPH
dextroamphetamine
DAT
dopamine transporter
DA
dopamine
ED50
median effective dose
IC50
half maximal inhibitory concentration
MPH
methylphenidate
NET
norepinephrine transporter
NE
norepinephrine

References

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