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Pharmacokinetics of methadone during maintenance treatment: adaptive changes during the induction phase
Abstract:
Deuterated methadone (M-d3) and GCMS were used to study the pharmacokinetics of methadone (M) during the induction stage of methadone maintenance treatment (MMT). A pulse dose of M-d3 was given on Days 1 and 25 of two dosage regimens, one with a continuous 30 mg dose (n = 6), and the other with 30 mg for 10 days, followed by 60 mg as the maintenance dose (n = 6). Plasma and urinary levels of M and M-d3 were measured throughout and plasma half-lives, oral bioavailabilities and volumes of distribution were calculated from the data of Days 1-2 and 24-26. The oral bioavailability of a methadone solution was found to be between 81 and 95%: elimination half-life in the beta-phase varied between 19 and 58 h; the volume of distribution was 4.1 +/- 0.65 l/kg; and total body clearance of M was 54-195 ml/min and its renal clearance 3.4-34 ml/min. A consistent finding was a lower urinary pH and increased renal clearance during the first month of treatment. The shorter elimination half-lives in those patients probably caused unacceptably high fluctuation in the body content of M during the 24 h dosage interval, and may have interfered therefore, with its therapeutic effectiveness.
Insights
Pharmacokinetics of methadone (M) during treatment induction were studied using deuterated methadone (M-d3). Shorter elimination half-lives may reduce methadone
Area of Science:
- Pharmacology
- Clinical Pharmacy
- Drug Metabolism
Background:
- Methadone maintenance treatment (MMT) is crucial for opioid use disorder.
- Understanding methadone pharmacokinetics during MMT induction is vital for optimizing patient outcomes.
- Variability in drug metabolism can impact treatment efficacy.
Purpose of the Study:
- To investigate the pharmacokinetics of methadone during the induction phase of MMT.
- To determine key pharmacokinetic parameters including oral bioavailability, half-life, and volume of distribution.
- To assess the impact of dosage regimens and treatment duration on methadone levels.
Main Methods:
- Utilized deuterated methadone (M-d3) as an internal standard for GCMS analysis.
- Administered pulse doses of M-d3 on Days 1 and 25 across two dosage regimens.
- Measured plasma and urinary methadone concentrations to calculate pharmacokinetic parameters.
Main Results:
- Oral bioavailability of methadone solution ranged from 81-95%.
- Elimination half-life varied significantly (19-58 hours), with shorter half-lives observed in some patients.
- Increased renal clearance and lower urinary pH were noted during the first month of treatment.
Conclusions:
- Shorter methadone elimination half-lives during MMT induction may lead to significant fluctuations in drug levels.
- These fluctuations could potentially compromise the therapeutic effectiveness of methadone.
- Further research is needed to address pharmacokinetic variability and optimize MMT dosing strategies.