Use of deuterium labeled methadone to measure steady state pharmacokinetics during methadone maintenance treatment

For many drugs the kinetics obtained from single dose studies are not those which apply in the steady state (SS) due to concentration- and time-dependent changes in distribution and elimination following continued dosage. The study of SS kinetics is therefore more relevant to clinical practice. In this communication a technique is presented for the study of methadone (M) SS kinetics using a pulse labeling with M-d3 and the use of mass fragmentography (MF) to measure both the unlabeled and labeled M in blood. Four subjects maintained on M for at least one year were admitted to a closed metabolic ward. The daily dose of M-d0 was substituted by M-d3 and M-d0 and M-d3 levels in plasma were followed for 48 hours using a precise (S.D. +- 4%) and sensitive (>16 pmoles/ml) MF technique. Plasma half-lives (T/sub 1/2/) for both M-d0 and M-d3 were calculated from samples obtained 8 to 24 hours following the dose of M-d3. The T/sub 1/2/ for M-d3 was shorter (21 +- 2.8 hours) when compared to the T/sub 1/2/ of M-d0 (67 +- 20 hours). In these subjects elevation of M-d0 levels were seen for 2 to 4 hours following M-d3 administration indicative of displacement by the pulse dose. These preliminary results indicate either the existence of multiple pools of M, or that M-d0 and M-d3 are not pharmacokinetically equivalent