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dl-threo-Methylphenidate is a highly efficacious drug for treating attention-deficit hyperactivity disorder (ADHD) that is currently administered as immediate- or controlled-release and osmotically controlled-released formulations. The drug exists as two enantiomers, d-threo-methylphenidate and l-threo-methylphenidate, with the former having been developed as a medication to treat ADHD in its own right. dl-threo-Methylphenidate undergoes enantioselective metabolism in the liver, which results in marked differences in the plasma concentrations of its isomers, depending on the route of administration and formulation. When dl-threo-methylphenidate is orally administered, the plasma concentrations of d-threo-methylphenidate are higher than those of l-threo-methylphenidate. However, with the recently developed methylphenidate transdermal system (MTS), 'first-pass' metabolism is circumvented and, as a consequence, plasma concentrations of d-threo-methylphenidate are consistent with those produced by oral formulations, but the relative concentrations of l-threo-methylphenidate are much higher, i.e. 50-60% of those of d-threo-methylphenidate. In this article, we review the pharmacokinetics and pharmacology of dl-threo-methylphenidate and its isomers to assess the extent to which their mechanism of action as noradrenaline (norepinephrine) and dopamine reuptake inhibitors is responsible for their efficacy and commonly occurring adverse effects. The major findings are that d-threo-methylphenidate and l-threo-methylphenidate share the same pharmacological profile as the parent racemate, i.e. catecholamine-selective reuptake inhibition with higher potency against dopamine versus noradrenaline reuptake in vivo. However, d-threo-methylphenidate is approximately 10-fold more potent than the l-isomer in this regard. For these drugs, their abilities not only to ameliorate the behavioural and cognitive dysfunctions in ADHD, but also to induce the common adverse effects of reduced appetite, nausea/vomiting and stomach ache, are almost certainly due to their ability to potentiate noradrenergic and/or dopaminergic function in the central and peripheral nervous systems. The sympathomimetic actions of ADHD drugs on cardiovascular function are currently an issue of concern. Since noradrenaline reuptake inhibition is the likely mediator for the effects of dl-threo-methylphenidate on blood pressure and heart rate, the more potent d-isomer will therefore be predominantly responsible. Motor and vocal tics are the other important adverse event to be considered in the treatment of ADHD. It is now accepted that tics are a frequently occurring behavioural manifestation of ADHD itself and the evidence for or against their exacerbation by treatment with dl-threo-methylphenidate or other stimulants remains highly contradictory. Focusing on the enantiomers of dl-threo-methylphenidate, it can be concluded that d-threo-methylphenidate, which is the more potent and abundant of the two isomers, is the major contributor of both efficacy and adverse effects, irrespective of the formulation or route of administration of the racemate. Moreover, for the oral, extended-release formulations of dl-threo-methylphenidate, the d-isomer represents the only pharmacologically active moiety when these medications are used in the clinic. With the MTS, plasma concentrations of l-threo-methylphenidate are higher than are achieved using oral formulations, but even in this case, it is likely that the contribution of this enantiomer to the efficacy and adverse effects of the racemate is no greater than 5-10% of the total.
Methylphenidate hydrochloride is a drug used in the treatment of narcolepsy and attention deficit hyperactivity disorders. This drug was nominated for study by the Food and Drug Administration and the National Cancer Institute because of its widespread use in human medicine and because of lack of data on its potential carcinogenicity. Oral administration is the most common route of human exposure. Toxicology and carcinogenicity studies were conducted by administering methylphenidate hydrochloride (USP grade) ad libitum in feed to groups of male and female F344/N rats and B6C3F1, mice for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were fed diets containing 0, 16, 62, 250, 1,000, or 4,000 ppm methylphenidate hydrochloride for 14 days. All rats survived to the end of the study. The final mean body weights of 4,000 ppm male and female rats were 9% lower than those of the controls. Absolute and relative liver weights of 4,000 ppm males and females were significantly greater than those of the controls. Clinical findings during the first week of the study included hyperactivity in 4,000 ppm males and females, but these animals appeared to be normal during the second week of treatment. No treatment-related gross lesions were observed; however, centrilobular hypertrophy was observed in 4,000 ppm males and females. 14-DAY STUDY IN MICE: Groups of five male and five female B6C3F1, mice were fed diets containing 0, 16, 62, 250, 1,000, or 4,000 ppm methylphenidate hydrochloride for 14 days. Three 4,000 ppm males died during the second week of the study; all other mice survived to the end of the study. The final mean body weight of 4,000 ppm females was 11% lower than that of the controls, and the mean body weight gains of 1,000 and 4,000 ppm males and females were also significantly lower than those of the controls. Absolute and relative liver weights of all exposed groups of males and of 4,000 ppm females were significantly greater than those of the controls. Hyperactivity was observed during the second week of the study in some 4,000 ppm males. Degeneration and necrosis of the renal tubule epithelium were observed in two 4,000 ppm males. Hepatocellular hypertrophy was observed in males and females exposed to 1,000 or 4,000 ppm and in males exposed to 250 ppm. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm methylphenidate hydrochloride for 13 weeks. There were no chemical-related effects on survival. Mean body weight gains of 500, 1,000, and 2,000 ppm males and females and of 250 ppm females were significantly lower than those of the controls. Final mean body weights of exposed males and females were similar to those of the controls. During the first week of the study, feed consumption by 2,000 ppm rats was less than that by controls, but during the remainder of the study feed consumption by exposed and control groups was similar. Rats exposed to 125, 250, 500, 1,000, or 2,000 ppm received approximate doses of 8, 15, 30, 70, or 130 mg methylphenidate hydrochloride per kilogram body weight per day (males) or 9, 18, 30, 70, or 150 mg/kg per day (females). Clinical findings in 1,000 and 2,000 ppm females included slight hypersensitivity to touch, hyperactivity, and increased vocalization during handling periods. Absolute and relative liver weights of 2,000 ppm males and females were significantly greater than those of the controls, as were the relative liver weights of 1,000 ppm males and females. No chemical-related differences in bone length, bone density, or nose-to-rump lengths were noted in males or females, nor were there treatment related histopathologic lesions. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1, mice were fed diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm methylphenidate hydrochloride for 13 weeks. There were no chemical-related effects on ed effects on survival. Final mean body weights of males exposed to 250, 500, 1,000, or 2,000 ppm and of 2,000 ppm females were significantly lower than those of the controls. The final mean body weights of other exposed male and female groups were similar to those of the controls. During the first week of the study, feed consumption by 2,000 ppm mice was less than that by controls; feed consumption by exposed groups was similar to that by the controls throughout the remainder of the study. Mice exposed to 125, 250, 500, 1,000, or 2,000 ppm received approximate doses of 15, 30, 70, 115, or 230 mg/kg per day (males) or 15, 30, 70, 125, or 260 mg/kg per day (females). No chemical-related clinical findings were observed. Absolute and relative liver weights of 1,000 and 2,000 ppm males and females were significantly greater than those of the controls, as were the relative liver weights of 125, 250, and 500 ppm males. Centrilobular hypertrophy and hepatocellular degeneration or necrosis were observed in males exposed to 500, 1,000, or 2,000 ppm methylphenidate hydrochloride. 2-YEAR STUDY IN RATS: Based on the increased liver weights and lower body weight gains in 2,000 ppm rats in the 13-week study, the high dose selected for the 2-year rat study was 1,000 ppm. Groups of 70 male and 70 female F344/N rats were fed diets containing 0, 100, 500, or 1,000 ppm methylphenidate hydrochloride for up to 2 years. As many as 10 male and 10 female rats per exposure group were evaluated at 9 or 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of exposed rats was similar to that of the controls at the end of the study. Mean body weights of 500 and 1,000 ppm males were 3% to 10% lower than those of the controls from week 30 to the end of the study; during the same time period, mean body weights of 500 and 1,000 ppm females were 4% to 24% less than those of the controls. Final mean body weights of rats exposed to 100, 500, or 1,000 ppm were 102%, 95%, or 90% (males) and 96%, 89%, or 78% (females) those of the controls. Rats exposed to 100, 500, or 1,000 ppm methylphenidate hydrochloride in feed received approximate doses of 5, 25, or 50 mg/kg per day (males and females). The only chemical-related clinical finding was an increased incidence of fighting among group-housed males exposed to 1,000 ppm. Hematology and Clinical Chemistry: No biologically significant differences in hematology or clinical chemistry parameters occurred at 9 or 15 months. Pathology Findings: In female rats exposed to 500 or 1,000 ppm, the incidence of mammary gland fibroadenomas was decreased (0 ppm, 15/49; 100 ppm, 13/50; 500 ppm, 6/ 48; 1,000 ppm, 5/50), and the decrease was considered to be related to chemical administration. No significant chemical-related increases in neoplasm incidences were observed in male or female rats. 2-YEAR STUDY IN MICE: Based on the liver toxicity and lower body weight gains observed in 1,000 and 2,000 ppm mice in the 13-week study, the high dose selected for the 2-year study was 500 ppm. Groups of 70 male and 70 female B6C3F1 mice were fed diets containing 0, 50, 250, or 500 ppm methylphenidate hydrochloride for 2 years. As many as 10 male and 10 female mice per exposure group were evaluated at 9 or 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of exposed mice was similar to that of the controls at the end of the study. Mean body weights of mice exposed to 250 or 500 ppm were 3% to 11% lower than those of the controls throughout much of the study; during the same time period, mean body weights of 250 ppm females were 3% to 7% lower than those of the controls. Final mean body weights of mice exposed to 50, 250, or 500 ppm were 97%, 89%, or 93% (males) and 98%, 93%, or 97% (females) that of the controls. Mice exposed to 50, 250, or 500 ppm methylphenidate hydrochloride in feed were estimated to have received 6, 30, or 60 mg/kg body weight per day (males) or 8, 40, or 80 mg/kg per day (females). There were no chemical related clinical findings. Hematology and Clinical Chemistry: No biologically significant differences in hematology or clinical chemistry parameters occurred at 9 or 15 months. Pathology Findings: The principal lesions associated with the administration of methylphenidate hydrochloride occurred in the liver. A few hepatocellular neoplasms were observed in control and exposed male mice at the 9-and 15-month interim evaluations, but the incidences in exposed groups were not significantly increased. At the end of the 2-year study, incidences of eosinophilic foci were increased in 500 ppm males and females. Increased incidences of hepatoblastoma occurred in 500 ppm males (0 ppm, 0/50; 50 ppm, 1/50; 250 ppm, 1/50; 500 ppm, 5/50). Increased incidences of hepatocellular adenoma also occurred in 500 ppm males (18/50, 18/50, 16/50, 29/50) and females (6/49, 10/48, 10/49, 28/50). The incidences of hepatocellular carcinoma were similar among control and exposed mice. GENETIC TOXICOLOGY: Methylphenidate hydrochloride was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). Methylphenidate hydrochloride was also tested for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. In the chromosomal aberrations tests, positive results were not consistently dependent upon the presence or absence of S9 activation. Sister chromatid exchanges were not increased in the presence of S9, but one laboratory did obtain a positive response without S9 by testing higher doses than were used in tests With S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of methylphenidate hydrochloride in male or female F344/ N rats receiving 100, 500, or 1,000 ppm. There was some evidence of carcinogenic activity of methylphenidate hydrochloride in male and female B6C3F1 mice based on the occurrence of hepatocellular neoplasms. Treatment of female rats with methylphenidate hydrochloride was associated with a decrease in the incidence of mammary gland fibroadenomas. Administration of methylphenidate hydrochloride to male and female mice resulted in increased incidences of eosinophilic foci. Synonyms: a-phenyl-2-piperidineacetic acid methyl ester hydrochloride; methylphenidylacetate hydrochloride; a-phenyl-a-(2-piperidyl)acetic acid methyl ester hydrochloride; methyl a-phenyl-a-(2-piperidyl)acetate hydrochloride
OBJECTIVE: The abuse potential of methylphenidate has been related to the drug's capacity to produce a rapid onset of blockade of the presynaptic dopamine transporter in the brain. An oral once-a-day osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would also produce a slower onset of blockade of the presynaptic dopamine transporter and would be associated with a lower risk for detection and likeability, compared to immediate-release methylphenidate. METHOD: Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Doses predicted to produce equivalent maximum concentration (C(max)) values were selected (40 mg of immediate-release methylphenidate and 90 mg of osmotic-release methylphenidate). Plasma d-methylphenidate levels and responses to detection/likeability questionnaire items were obtained hourly for 10 hours after administration of methylphenidate on two separate occasions for each subject. Dopamine transporter receptor occupancies were measured at hours 1, 3, 5, and 7 by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography. RESULTS: Despite similar C(max) values for both formulations, osmotic-release methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS dopamine transporter occupancy, and no detection/likeability, compared with immediate-release methylphenidate. CONCLUSIONS: The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.
RATIONALE: The psychostimulant dl-threo-methylphenidate is commonly used to treat attention deficit-hyperactivity disorder (ADHD). Consistent with its effects in ADHD patients, racemic methylphenidate antagonizes behavioral hyperactivity in several animal models of ADHD, including juvenile rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of forebrain dopamine projections. The enantiomers of methylphenidate differ markedly in stimulant potency but have not been compared in the 6-OHDA lesion model. OBJECTIVE: Locomotor-inhibiting effects of methylphenidate enantiomers were compared in 6-OHDA-lesioned rats to test the hypothesis that d-methylphenidate is more potent than dl- and l-methylphenidate. METHODS: Selective dopamine lesions were made using 6-OHDA (100 microg, intracisternal, IC) on postnatal day (PD) 5 after desipramine (25 mg/kg, SC) pretreatment to protect noradrenergic neurons. Effects of d-, l- and dl-threo-methylphenidate on locomotor activity of lesioned and sham control rats were quantified at PD 23-27. RESULTS: Lesioning yielded robust motor hyperactivity at PD 23-27. Both d- and dl-methylphenidate stimulated locomotor activity in intact rats, and inhibited activity in lesioned rats. l-Methylphenidate did not affect locomotor activity in either lesioned rats or controls. d-Methylphenidate (ED(50)=1.66 mg/kg) was 3.3 times more potent than dl-methylphenidate (ED(50)=5.45 mg/kg) in reducing locomotor hyperactivity in lesioned rats. In addition, pretreatment of lesioned rats with l-methylphenidate significantly reduced the motor inhibiting effects of d-methylphenidate. CONCLUSIONS: The more active enantiomer, as predicted, was d-methylphenidate, but the l-enantiomer interfered with its effects, suggesting that clinical potency of d-methylphenidate may be more than twice that of the racemate.
Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD). OROS (methylphenidate HCl) is an osmotic controlled-release delivery system designed for once-daily oral dosing. The pharmacokinetics of OROS (methylphenidate HCl) 18 mg qd, sustained-release (SR) methylphenidate 20 mg qd, and the immediate-release (IR) formulation given as three 5 mg doses every 4 hours (tid) were compared in adults. In addition, the single- and multiple-dose pharmacokinetics of the OROS formulation were studied. Following OROS (methylphenidate HCl), there was a gradual increase in the mean methylphenidate plasma concentrations with peak concentrations noted at 6 to 8 hours. With the SR formulation, peak plasma concentrations were noted at approximately 4 hours. Following the IR regimen, methylphenidate plasma concentrations fluctuated in tandem with oral dosing; peak concentrations were noted at 6.5 hours. The terminal half-life of methylphenidate was similar for the three formulations. The dose-normalized methylphenidate Cmax for OROS (methylphenidate HCl) was significantly lower than for IR and SR methylphenidate. The bioavailability of methylphenidate and PPA from OROS (methylphenidate HCl) relative to the IR and SR formulations was complete. Mean methylphenidate AUC and terminal half-life were similar after single (32.9 ng.h/mL and 3.9 hours) and multiple doses (35.2 ng.h/mL and 3.9 hours) of OROS (methylphenidate HCl).
Methylphenidate is prescribed for over 90% of children in the US diagnosed as having attention-deficit hyperactivity disorder (ADHD). Although ADHD has been widely studied, the use of methylphenidate in ADHD still poses a number of unresolved questions, including its pharmacodynamic characteristics (drug concentration-effect relationship) and the effect of long term treatment on the patient's psychopathology later in life. The objective of this review is to provide an analysis of the pharmacokinetic-pharmacodynamic properties and therapeutic effectiveness of methylphenidate that may help to answer some of these questions. Methylphenidate has 2 chiral centres, but the drug used in therapy comprises only the threo pair of enantiomers. d-threo-Methylphenidate is more potent than the l-enantiomer. Methylphenidate is administered as a racemic mixture that undergoes stereoselective clearance. Methylphenidate is a short-acting stimulant with a duration of action of 1 to 4 hours and a pharmacokinetic half-life of 2 to 3 hours. Maximum drug concentration after oral administration occurs at about 2 hours. Methylphenidate is absorbed well from the gastrointestinal tract and easily passes to the brain. Methylphenidate is efficacious for short term treatment for children with ADHD. Its mechanism of action is not understood, but may be associated with its influence on multiple neurotransmitters, especially the release and reuptake of dopamine in the striatum. There is marked individual variability in the dose-response relationship for methylphenidate, and therefore dosage must be titrated for optimal effect and avoidance of toxicity in each child. It is unclear whether this variability is predominantly pharmacokinetic or pharmacodynamic. If variable stereoselective metabolism occurs clinically, therapeutic drug monitoring of methylphenidate will require the application of chiral assay methods for the analysis of the active component, d-threo-methylphenidate. It is difficult to predict which children will have a favourable response to methylphenidate. Nonetheless, several studies have been published linking the severity of ADHD in children with improved clinical response to methylphenidate. The use of individual single-blind medication trials may be a practical solution to this problem. Additionally, the targeted condition warrants careful consideration, since different conditions (e.g. misbehaviour or poor academic performance) may require different regimens. Further studies of the relationship between the pharmacokinetic and pharmacodynamic properties of methylphenidate are required to allow the development of optimal dosage regimens.
BACKGROUND: The purposes of this study were to investigate the pharmacokinetics of methylphenidate hydrochloride (Ritalin) in the human brain, to compare them with those of cocaine, and to evaluate whether cocaine and methylphenidate compete for the same binding sites. METHODS: We used positron emission tomography to measure the temporal and spatial distribution of carbon 11 (11C)-labeled methylphenidate. These results were compared with those obtained previously for [11C]cocaine. Eight healthy male subjects, 20 to 51 years of age, were scanned with [11C]methylphenidate. Three were tested twice to assess test-retest variability, four were tested at baseline and after administration of methylphenidate, and one was tested with [11C]methylphenidate and [11C]cocaine. Two baboons were scanned to evaluate whether there was competition between cocaine and methylphenidate for the same binding sites in the brain. RESULTS: The uptake of [11C]methylphenidate in the brain was high (mean +/- SD, 7.5% +/- 1.5%), and the maximal concentration occurred in striatum. Pretreatment with methylphenidate decreased binding only in striatum (40%). Although the regional distribution of [11C]methylphenidate, was identical to that of [11C]cocaine and they competed with each other for the same binding sites, these two drugs differed markedly in their pharmacokinetics. Clearance of [11C]methylphenidate from striatum (90 minutes) was significantly slower than that of [11C]cocaine (20 minutes). For both drugs, their fast uptake in striatum paralleled the experience of the "high." For methylphenidate, the high decreased very rapidly despite significant binding of the drug in the brain. In contrast, for cocaine, the decline in the high paralleled its fast rate of clearance from the brain. CONCLUSION: We speculate that because the experience of the high is associated with the fast uptake of cocaine and methylphenidate in the brain, the slow clearance of methylphenidate from the brain may serve as a limiting factor in promoting its frequent self-administration.
BACKGROUND: The duration of action of the immediate-release formulation of methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of methylphenidate had reduced efficacy compared with immediate-release methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance. METHODS: Children with attention-deficit/hyperactivity disorder were evaluated in a laboratory school to characterize onset and duration of the effect of a variety of methylphenidate regimens. In a proof-of-concept study, an experimental ascending profile was established by an initial bolus followed by small increasing doses of immediate-release methylphenidate in capsules administered every 30 minutes for 8 hours. Two proof-of-product studies of a new oral once-a-day formulation to deliver methylphenidate by an osmotic pump process based on OROS (ALZA Corp, Mountain View, Calif) technology (hereafter referred to "OROS-methylphenidate") were conducted: a pharmacokinetic study and a pharmacodynamic study. RESULTS: The experimental ascending profile matched the effect of the standard regimen of methylphenidate, 3 times daily. In the pharmacokinetic study, OROS-methylphenidate treatment produced a rapid rise followed by increasing plasma concentrations that peaked 7 to 9 hours after administration. In the pharmacodynamic study, OROS-methylphenidate treatment matched the 3 times daily dosing of methylphenidate for onset and duration of efficacy. CONCLUSIONS: These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of methylphenidate) into clinical application (the selection of a new drug delivery pattern for methylphenidate). This approach produced a new product (OROS-methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy (10-12 hours) after a single administration in the morning.
The role of MK-801's locomotor effect in blocking the development of sensitization to methylphenidate was investigated utilizing a computerized locomotor activity monitoring system. After 7 days of acclimation to a 12:12 light-dark cycle (lights on at 07:00), male Sprague-Dawley rats (n=62) were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days of recording served as a baseline for each rat, and on day 3 each rat received a saline injection. On days 4 to 9 rats were randomly divided into seven groups: Rats received either six daily s.c. injections of methylphenidate (2.5 mg/kg; Group 1), or six daily i.p. injections of 0.30 mg/kg, 0.05 mg/kg MK-801 (Groups 2 and 3, respectively); two MK-801 pre-treatment groups received a single i.p. injection of 0.05, or 0.30 mg/kg MK-801 one hour prior to 2.5 mg/kg methylphenidate (n=8 each) on day 4 followed by five daily injections of 2.5 mg/kg methylphenidate; and finally, two cotreatment groups received a challenge dose of 2.5 mg/kg methylphenidate on day 4 followed by either 0.05 or 0.30 mg/kg MK-801 i.p. one hour prior to 2.5 mg/kg methylphenidate from days 5 to 9. All groups were allowed five days of no treatment before being re-challenged on day 15 with the same treatment they received on day 4. Methylphenidate and 0.30 mg/kg MK-801 sensitized to their own locomotor effects, but 0.05 mg/kg MK-801, which had no acute motor effects, did not. The administration of MK-801 (0.30 mg/kg) prior to methylphenidate either singly on day 4, or coadministered throughout the repeated methylphenidate treatment phase, blocked the development of sensitization to methylphenidate. However, MK-801 at 0.05 mg/kg delayed the development of sensitization when co-administered on days 5 to 9, but a single injection 1 h prior to methylphenidate on day 4 did not prevent sensitization to subsequent methylphenidate administration. In conclusion, MK-801 prevents sensitization to methylphenidate; motor stimulation by MK-801 is not necessary for short-term prevention or delay of sensitization to methylphenidate but may be necessary for a persistent blockade of sensitization.
OBJECTIVES: To determine methylphenidate use in children aged 2 to 13 years. To provide age- and sex-specific estimates of methylphenidate initiation and cessation during a 2-year period. METHOD: Data from 2 cycles of a Canadian household survey yielded a sample of over 10 000 children aged 2 to 11 years at Cycle 1 who continued to participate at Cycle 2. We used logit modelling to estimate Cycle 2 methylphenidate use, methylphenidate use over a 2-year period, and methylphenidate initiation and cessation from Cycles 1 to 2. RESULTS: In 1996 and 1997, methylphenidate use ranged from 0.32% to 6.31% among children aged 4 to 13 years. School-aged boys were more likely than girls to use methylphenidate. Odds were greater for boys aged 6 to 7 years than for boys aged 4 to 5 years; they were also greater for boys aged 10 to 11 years than for boys aged 12 to 13 years. Almost 1% of children used methylphenidate at both data cycles. Odds of Cycle 2 methylphenidate use were 135 times greater for children using methylphenidate at Cycle 1, compared with nonusers. Methylphenidate initiation ranged from 0.20% to 3.34%, and school-aged boys had higher initiation rates than girls. Cessation rates ranged from 18% to78%, and there were no statistically significant differences by age and sex. CONCLUSIONS: Methylphenidate prevalence findings are consistent with past studies. We found an age-by-sex interaction on methylphenidate use. We also found both continuity and discontinuity in methylphenidate use.
Methylphenidate hydrochloride (HCl) is frequently used for the treatment of attention deficit/hyperactivity disorder (ADHD). A study was conducted in healthy subjects to evaluate the dose-ranging pharmacokinetics of 18, 36, and 54 mg methylphenidate HCl delivered using an oral, osmotic, controlled-release formulation (OROS). Plasma concentrations of l-methylphenidate were 40-fold lower than those of d-methylphenidate, whereas plasma concentrations of d-alpha-phenyl-2-piperidine acetic acid (d-PPA) and l-PPA, the major metabolite of methylphenidate, were comparable. Mean AUCinf values for d-methylphenidate were 42.2, 80.9, and 120 ng.h/mL for the 18, 36, and 54 mg doses, respectively, increasing dose proportionally. AUCinf values for l-methylphenidate were only approximately 1% of d-methylphenidate (0.43, 0.96, and 1.82 ng.h/mL for the 18, 36, and 54 mg dose groups, respectively). In contrast, AUCinf values of d- and l-PPA were comparable. The dose-normalized d- and l-methylphenidate plasma concentration-time profiles for the three treatment groups were superimposable. Similarly, dose-normalized plasma concentrations of d- and l-PPA were superimposable. Methylphenidate metabolism, measured as the ratio of d-methylphenidate AUCinf to d-PPA AUCinf and as l-methylphenidate AUCinf to l-PPA AUCinf, was similar for the three dose groups, indicating that methylphenidate metabolism was not affected by increasing dose. OROS (methylphenidate HCl) exhibits dose-proportional and linear pharmacokinetics.
Blockade of sensitization to methylphenidate by a single injection of MK-801 was investigated using a computerized activity monitoring system. Male Sprague-Dawley rats were housed in test cages and motor activity was recorded continuously for 16 days. After 2 days of baseline recording and a saline injection on day 3, the rats were randomly divided into four experimental groups. All received 2.5 mg/kg of methylphenidate (s.c.) once a day from days 4 to 9, then after five days of no treatment, they were re-challenged with 2.5 mg/kg of methylphenidate on day 15. One group received only methylphenidate, while the other three groups also received a single i.p. injection of MK-801 (0.30 mg/kg) either 24 h (day 3) or 1 h prior to the first of the six methylphenidate injections (day 4), or 1 h prior to the second methylphenidate injection (day 5). A single injection of MK-801 on day 4 (1 h prior to methylphenidate) blocked the development of sensitization to methylphenidate, since a sensitized response could not be elicited six days after cessation of repeated methylphenidate administration (day 15). However, sensitization to methylphenidate still occurred in the groups receiving MK-801 (0.30 mg/kg) on day 5, indicating that the mechanism by which a single injection of MK-801 disrupts sensitization to methylphenidate is sensitive to timing and is not a direct long-term effect. In conclusion, a single injection of MK-801 persistently blocks the development of sensitization to methylphenidate only if it is given with methylphenidate on the first day of the repetitive treatment phase.
Methylphenidate is an important stimulant prescribed to treat attention-deficit hyperactivity disorder. It has two chiral centers, but most current commercial formulations consist of the racemic mixture of the threo pair of methylphenidate isomers (d-, l-threo-methylphenidate). The d-isomer is the pharmacologically active component. Numerous studies reported that oral administration of the methylphenidate racemate undergoes first-pass, stereoselective clearance in humans with l-methylphenidate being eliminated faster than d-methylphenidate. Accordingly, the kinetics of hydrolysis of individual enantiomers by purified native and recombinant human liver carboxylesterases CES1A1 and CES2 and a colon isoenzyme CES3 were examined with a liquid chromatography/mass spectrometry assay. The expression of CES1A1, CES2, and CES3 in Sf9 cells and the methods for purification of the three isoenzymes are reported. CES1A1 has a high catalytic efficiency for both d- and l-enantiomers of methylphenidate. No catalytic activity was detected with CES2 and CES3 for either enantiomer. The catalytic efficiency of CES1A1 for l-methylphenidate (k(cat)/K(m) = 7.7 mM(-1) min(-1)) is greater than that of d-methylphenidate (k(cat)/K(m) = 1.3-2.1 mM(-1) min(-1)). Hence, the catalytic efficiency of CES1A1 for methylphenidate enantiomers agrees with stereoselective clearance of methylphenidate reported in human subjects. Both enantiomers of methylphenidate can be fit into the three-dimensional model of CES1A1 to form productive complexes in the active site. We conclude that CES1A1 is the major enzyme responsible for the first-pass, stereoselective metabolism of methylphenidate.
PURPOSE: The treatment patterns of and use of emergency room services by patients with attention-deficit/hyperactivity disorder (ADHD) who initiated therapy with thrice-daily, immediate-release (IR) methylphenidate versus once-daily, extended-release (ER) oral system methylphenidate were studied. METHODS: Using a large claims database, patients who were newly initiated on either ER methylphenidate or IR methylphenidate were retrospectively identified. Analysis of covariance was used to examine differences in treatment patterns between individuals who initiated therapy on ER methylphenidate and those who initiated therapy on IR methylphenidate. Multivariate regressions were used to examine the probability of visiting the emergency room and the number of visits to the emergency room. RESULTS: Of the 5939 patients who met the inclusion criteria, 4785 were initiated on ER methylphenidate and 1154 were initiated on IR methylphenidate. Significantly fewer patients initiated on ER methylphenidate had a 15- or 30-day gap in therapy or switched to another ADHD medication (p < 0.0001 for all comparisons). In addition, patients initiated on the ER formulation had a significantly longer duration of therapy than did those who received IR methylphenidate (p < 0.0001). Patients who received initial treatment with ER methylphenidate were also significantly less likely to visit an emergency room (odds ratio, 0.79; p = 0.01) and had, on average, 0.21 fewer visit to the emergency room (p = 0.0101). CONCLUSION: A retrospective analysis of a patient database demonstrated that initial treatment with ER methylphenidate for patients with ADHD was associated with longer treatment periods, fewer switches in therapy, increased patient adherence, and a lower usage rate of emergency room services compared with initial treatment with IR methylphenidate.
Positron emission tomography was used to compare the pharmacokinetics of [11C]methylphenidate in the human brain with the temporal course of the subjective and cardiovascular effects observed after intravenous methylphenidate (0.5 mg/kg). Four subjects were tested twice with [11C]methylphenidate, at baseline and after methylphenidate. All subjects showed almost identical uptake of 11C labeled drug in brain, as well as a very similar decrease in binding of [11C]methylphenidate in basal ganglia, after pretreatment with methylphenidate. In contrast, the magnitude of the behavioral and cardiovascular changes induced by methylphenidate varied among the subjects. The temporal course for methylphenidate effects paralleled closely the pharmacokinetics of [11C]methylphenidate in brain for the perception of "restlessness" and for changes in systolic blood pressure and heart rate. In contrast, methylphenidate induced "high", "anxiety" and changes in diastolic blood pressure decreased rapidly despite long lasting binding of the drug in brain. These results indicate that binding of methylphenidate in brain does not appear to predict individual responses to the drug and that more than one neurotransmitter and/or adaptation process are likely to be involved in the behavioral and cardiovascular effects of methylphenidate.
Ethylphenidate is formed by metabolic transesterification of methylphenidate and ethanol. Study objectives were to (a) establish that ethylphenidate is formed in C57BL/6 (B6) mice; (b) compare the stimulatory effects of ethylphenidate and methylphenidate enantiomers; (c) determine methylphenidate and ethylphenidate plasma and brain distribution and (d) establish in-vitro effects of methylphenidate and ethylphenidate on monoamine transporter systems. Experimental results were that: (a) coadministration of ethanol with the separate methylphenidate isomers enantioselectively produced l-ethylphenidate; (b) d and dl-forms of methylphenidate and ethylphenidate produced dose-responsive increases in motor activity with stimulation being less for ethylphenidate; (c) plasma and whole-brain concentrations were greater for ethylphenidate than methylphenidate and (d) d and DL-methylphenidate and ethylphenidate exhibited comparably potent low inhibition of the dopamine transporter, whereas ethylphenidate was a less potent norepinephrine transporter inhibitor. These experiments establish the feasibility of the B6 mouse model for examining the interactive effects of ethanol and methylphenidate. As reported for humans, concurrent exposure of B6 mice to methylphenidate and ethanol more readily formed l-ethylphenidate than d-ethylphenidate, and the l-isomers of both methylphenidate and ethylphenidate were biologically inactive. The observed reduced stimulatory effect of d-ethylphenidate relative to d-methylphenidate appears not to be the result of brain dispositional factors, but rather may be related to its reduced inhibition of the norepinephrine transporter, perhaps altering the interaction of dopaminergic and noradrenergic neural systems.