RESUMEN
Scarce data are available on methylphenidate (MPH) plasma concentrations reached after doses higher than 180 mg. The interindividual and intraindividual variability in the exposure of MPH and ritalinic acid (RA) enantiomers was examined in 28 patients with ADHD and substance use disorders, with MPH daily doses between 30 and 600 mg (median 160 mg). MPH and RA plasma concentrations were analysed with an enantioselective LC-MS/MS method. d-MPH plasma concentration/dose varied 25-fold between subjects but was reasonably stable within an individual. Twelve subjects had quantifiable l-MPH plasma concentrations, which accounted for up to 48% of the total MPH plasma concentration. The less active l-MPH enantiomer could, in individuals with low carboxylesterase 1 (CES1) activity, contribute significantly to the total MPH plasma drug concentration and hamper the estimation of the exposure to the more active d-MPH enantiomer. However, the high correlation between the total (d + l) RA/MPH metabolic ratio and the d-RA/d-MPH metabolic ratio (rs = 0.94) indicates that the ratio based on non-enantioselective analysis could be used as a marker of CES1 activity. Whether this holds true for subjects with aberrant metabolism due to genetic variants or during concomitant treatment with inhibitors or inducers of the enzyme remains to be studied.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Estimulantes del Sistema Nervioso Central , Metilfenidato , Trastornos Relacionados con Sustancias , Adulto , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Hidrolasas de Éster Carboxílico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Cromatografía Liquida , Humanos , Metilfenidato/uso terapéutico , Estereoisomerismo , Espectrometría de Masas en TándemRESUMEN
PURPOSE: The primary aim of this study was to explore the potential of alternative sampling matrices for methylphenidate by assessing the correlations between dl-threo-methylphenidate and dl-threo-ritalinic acid concentrations in exhaled breath and oral fluid with those in plasma, in repeated samples collected after a single oral dose of methylphenidate. The secondary aim was to study the enantioselective pharmacokinetics of methylphenidate in plasma, with a focus on interindividual variability in the metabolism of methylphenidate to ritalinic acid. METHODS: Twelve healthy volunteers received a single oral dose of dl-threo-methylphenidate (Ritalin® capsules, 20 mg). Venous blood samples were collected for 24 h, and plasma analyzed for threo-enantiomers of methylphenidate and ritalinic acid with LC-MS/MS. Repeated sampling of exhaled breath, using a particle filter device, and of non-stimulated oral fluid, using a felt pad device, was also performed. Exhaled breath and oral fluid were analyzed with a non-enantioselective LC-MS/MS method for dl-threo-methylphenidate and dl-threo-ritalinic acid. RESULTS: In all subjects, d-threo-methylphenidate was detectable in plasma for at least 15 h after the dose with a biphasic profile. l-threo-Methylphenidate was measurable in only five subjects and in most cases in low concentrations. However, one female subject displayed a biphasic concentration-time profile for l-threo-methylphenidate. This subject also had the highest d-threo-methylphenidate AUC (191 ng*h/mL versus 32-119 ng*h/mL in the other subjects). d-threo-Ritalinic acid concentrations were on average 25-fold higher (range 6-126) than the corresponding d-threo-methylphenidate concentrations. Single-time point plasma concentration ratios between d-threo-ritalinic acid and d-threo-methylphenidate 1.5-12 h after dose correlated highly (r = 0.88-0.98) with the d-threo-ritalinic acid AUC/d-threo-methylphenidate AUC ratio. In eleven subjects, dl-threo-methylphenidate in oral fluid mirrored the biphasic profile of methylphenidate (sum of d- and l-threo-enantiomers) in plasma, but the concentrations in oral fluid were on average 1.8 times higher than in plasma. dl-threo-Methylphenidate was detected in exhaled breath in all subjects, but there was no consistent concentration-time pattern. CONCLUSIONS: In some subjects, the pharmacologically less active l-threo-enantiomer may contribute to the total plasma methylphenidate concentrations. Monitoring methylphenidate concentrations without enantiomeric determination carries the risk of missing such subjects, which might affect how the plasma concentrations of methylphenidate are interpreted and used for clinical decision making. The use of exhaled breath and oral fluid to assess medication adherence to MPH in patients with ADHD warrants further studies.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacocinética , Metilfenidato/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Pruebas Respiratorias/métodos , Estimulantes del Sistema Nervioso Central/administración & dosificación , Cromatografía Liquida , Femenino , Humanos , Masculino , Cumplimiento de la Medicación , Metilfenidato/administración & dosificación , Metilfenidato/análogos & derivados , Estereoisomerismo , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
BACKGROUND: Substance use disorders (SUDs) are common comorbidities of Attention Deficit Hyperactivity Disorder (ADHD). The most commonly prescribed medication for ADHD is methylphenidate. The clinical response to methylphenidate may be monitored against DSM-5 symptomatology, rating scales or interviews. AIMS: To evaluate the use of perceptual and cognitive processing speed measures to monitor methylphenidate effects in adults with ADHD and SUD. METHODS: A Quick Test of Cognitive Speed (AQT) monitored perceptual and cognitive processing speed in 28 adults with ADHD and SUD on treatment with methylphenidate before and after the morning dose. RESULTS: Twenty-six patients responded on AQT after the morning dose of methylphenidate. One-way ANOVA indicated significant treatment effects for color, form, and color-form combination naming, but not for shift cost values. Before the morning dose of methylphenidate, 92% were identified by cutoff time criteria for longer-than-normal processing times. After the morning dose of methylphenidate, 65% obtained color and form measures in the normal range for age peers. Only 35% obtained color-form processing measures in the normal range. Inter-individual response variability before medication intake was considerably larger than previously reported in studies of adults with ADHD only. CONCLUSION: Proportionally, fewer adults with ADHD and SUD exhibited normalization of processing speed than previously observed for adults with ADHD without SUD. A potential clinical implication of the present study is that the AQT test may be used as a tool for dose-adjustment of central stimulants in the treatment of adults with ADHD and SUD.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Metilfenidato/uso terapéutico , Tiempo de Reacción/efectos de los fármacos , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Adolescente , Adulto , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Estimulantes del Sistema Nervioso Central/farmacología , Cognición/efectos de los fármacos , Cognición/fisiología , Comorbilidad , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Masculino , Metilfenidato/farmacología , Persona de Mediana Edad , Proyectos Piloto , Tiempo de Reacción/fisiología , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/psicología , Resultado del Tratamiento , Adulto JovenRESUMEN
In the treatment of substance use disorder, regular laboratory-based testing has the dual purpose of monitoring compliance with the prescribed medication and abstention from medically non-motivated substances (ie, drug abuse screening). The principal specimen for testing is urine, but collection of urine has some disadvantages, for example being more time-consuming and more intrusive compared to other matrices. There is also the risk of adulteration. This project compared exhaled breath and oral fluid as alternative matrices for drug abuse screening in patients with substance use disorder. All 51 subjects included in the study were enrolled at the Drug Addiction Emergency Unit in Stockholm. Exhaled breath, oral fluid, and urine samples were collected together with a self-report. Of all 117 self-reported drug intakes during the previous week, 72% were confirmed in urine, 73% in oral fluid and 39% in exhaled breath. In 31% of the subjects, additional substances other than those self-reported were detected analytically. For substance abuse screening, urine had the highest detection rate for buprenorphine, cannabis, and benzodiazepines, while oral fluid had the highest detection rate for amphetamines and methadone. Exhaled breath showed the highest detection rate of all matrices for cocaine. To identify significant differences in detection rates between the matrices future studies with larger sampling sizes are needed. Both oral fluid and exhaled breath are viable alternative specimens to urine, depending on the circumstances and purpose of the testing.