Pharmacokinetics of methylphenidate and ritalinic acid in plasma correlations with exhaled breath and oral fluid in healthy volunteers

Abstract 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.

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First report on the pharmacokinetics of tramadol and O-desmethyltramadol in exhaled breath compared to plasma and oral fluid after a single oral dose

Biochemical Pharmacology ◽

10.1016/j.bcp.2015.09.008 ◽

2015 ◽

Vol 98 (3) ◽

pp. 502-510 ◽

Cited By ~ 19

Author(s):

Markus R. Meyer ◽

Staffan Rosenborg ◽

Marta Stenberg ◽

Olof Beck

Keyword(s):

Oral Dose ◽

Single Oral Dose ◽

Oral Fluid ◽

Exhaled Breath ◽

First Report

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Faculty Opinions recommendation of Decreased [18F]MPPF binding potential in the dorsal raphe nucleus after a single oral dose of fluoxetine: a positron-emission tomography study in healthy volunteers.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1115675.571742 ◽

2008 ◽

Author(s):

Ahmad Hariri ◽

Patrick Fisher

Keyword(s):

Positron Emission Tomography ◽

Oral Dose ◽

Healthy Volunteers ◽

Single Oral Dose ◽

Dorsal Raphe Nucleus ◽

Raphe Nucleus ◽

Emission Tomography ◽

Positron Emission Tomography Study ◽

Binding Potential ◽

Positron Emission

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Urinary Excretion and Bactericidal Activities of a Single Oral Dose of 400 Milligrams of Fleroxacin versus a Single Oral Dose of 800 Milligrams of Pefloxacin in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.7.1659 ◽

1998 ◽

Vol 42 (7) ◽

pp. 1659-1665 ◽

Cited By ~ 15

Author(s):

Kurt G. Naber ◽

Ursula Theuretzbacher ◽

Martina Kinzig ◽

Orlin Savov ◽

Fritz Sörgel

Keyword(s):

Oral Dose ◽

Healthy Volunteers ◽

Single Oral Dose ◽

E Coli ◽

Wide Range ◽

The Mean ◽

Bactericidal Activities ◽

Tract Infections ◽

Time Kill ◽

Randomized Crossover Study

ABSTRACT Twelve healthy volunteers participated in this randomized crossover study to compare the concentrations and recovery levels of fleroxacin and pefloxacin in urine and to assess their bactericidal activities against 12 strains of urinary pathogens with different susceptibilities over a wide range of MICs. The volunteers received a single oral dose of 400 mg of fleroxacin or 800 mg of pefloxacin. The mean cumulative renal excretion of unchanged fleroxacin,N-demethyl-fleroxacin, and N-oxide-fleroxacin accounted for 67, 7, and 6% of the total dose, respectively. The total urinary recovery of pefloxacin and the active metabolite norfloxacin was 34%. In the time-kill and the urinary bactericidal titer (UBT) studies, only the subjects’ urine not supplemented with broth was used. With most tested organisms and both quinolones it took more than 8 h to achieve a reduction in CFU of 99.9% (3 log units). Overall, there was a good correlation between UBTs and MICs for the strains. Against Escherichia coli ATCC 25922 the median UBTs were similar for both antibiotics and at least 1:8 for 96 h; against the E. coli strain for which the MIC was 0.5 μg/ml the UBT was at least 1:4 for 48 h. The UBTs of both drugs against Klebsiella pneumoniae were at least 1:16 for 72 h. The UBTs for Staphylococcus aureus (the MIC for which was 16 μg/ml) of both antibiotics were low, and in some of the samples, no bactericidal titers were observed. UBTs for Proteus mirabilis of pefloxacin are significantly higher than those of fleroxacin. For Pseudomonas aeruginosa the median UBTs were present for the 24-to-48-h interval. The same is true forEnterococcus faecalis. Against Staphylococcus saprophyticus, UBTs were present for at least 48 h with both quinolones. Overall, a single oral dose of 400 mg of fleroxacin exhibits UBTs comparable to those of 800 mg of pefloxacin. Therefore, it may be expected that half of the dose of fleroxacin gives comparable results in the treatment of urinary tract infections; this should be substantiated in comparative clinical trials.

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C14.4 Concentrations in plasma, urinary excretion, and bactericidal activity of levofloxacin (500) versus those of ciprofloxacin (500 milligrams) in healthy volunteers receiving a single oral dose

International Journal of Antimicrobial Agents ◽

10.1016/s0924-8579(05)80279-1 ◽

2005 ◽

Vol 26 ◽

pp. S98

Keyword(s):

Oral Dose ◽

Urinary Excretion ◽

Healthy Volunteers ◽

Single Oral Dose ◽

Bactericidal Activity

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Pharmacokinetic (PK) study of a single oral dose of NEPA in Chinese healthy volunteers (HVs)

Annals of Oncology ◽

10.1093/annonc/mdx388.015 ◽

2017 ◽

Vol 28 ◽

pp. v548 ◽

Cited By ~ 1

Author(s):

R. Chen ◽

S. Chessari ◽

C. Lanzarotti ◽

A. Bernareggi ◽

P. Hu

Keyword(s):

Oral Dose ◽

Healthy Volunteers ◽

Single Oral Dose

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Urinary Bactericidal Activity of Extended-Release Ciprofloxacin (1,000 Milligrams) versus Levofloxacin (500 Milligrams) in Healthy Volunteers Receiving a Single Oral Dose

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00477-06 ◽

2006 ◽

Vol 50 (11) ◽

pp. 3947-3949 ◽

Cited By ~ 14

Author(s):

Florian M. E. Wagenlehner ◽

Martina Kinzig-Schippers ◽

Uwe Tischmeyer ◽

Christine Wagenlehner ◽

Fritz Sörgel ◽

...

Keyword(s):

Oral Dose ◽

Healthy Volunteers ◽

Single Oral Dose ◽

Bactericidal Activity ◽

Proteus Mirabilis ◽

Extended Release

ABSTRACT Twelve volunteers received a single oral dose of 1,000 mg extended-release (XR) ciprofloxacin versus 500 mg levofloxacin to assess urinary bactericidal titers (UBTs) against common uropathogens. Areas under UBT-time curves were significantly larger for Proteus mirabilis with XR ciprofloxacin and for staphylococci with levofloxacin.

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Phase I and Pharmacokinetic Study of Temozolomide on a Daily-for-5-Days Schedule in Patients With Advanced Solid Malignancies

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.8.2604 ◽

1999 ◽

Vol 17 (8) ◽

pp. 2604-2604 ◽

Cited By ~ 83

Author(s):

Lisa A. Hammond ◽

John R. Eckardt ◽

Sharyn D. Baker ◽

S. Gail Eckhardt ◽

Margaret Dugan ◽

...

Keyword(s):

Oral Dose ◽

Single Oral Dose ◽

Hematologic Toxicity ◽

Targeted Therapeutics ◽

Time Curve ◽

Concentration Time ◽

Solid Malignancies ◽

Cumulative Rate ◽

Heavily Pretreated ◽

Higher Doses

PURPOSE: To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients. PATIENTS AND METHODS: Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m2/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses. RESULTS: Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m2/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (ClS/F) averaging 1.8 hours and 115 mL/min/m2, respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in ClS/F was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration (median 16 v 9.5 μg/mL, P = .0084) and area under the concentration-time curve (median 36 v 23 μg-h/mL, P = .0019) values on day 5. CONCLUSION: Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m2/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.

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