PT  - JOURNAL ARTICLE
AU  - ANNE L. CAHILL
AU  - MARK P. HOORNSTRA
AU  - FEDOR MEDZIHRADSKY
TI  - Active Transport of Methadone in Synaptosomes
DP  - 1979 Sep 01
TA  - Molecular Pharmacology
PG  - 587--600
VI  - 16
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/16/2/587.short
4100  - http://molpharm.aspetjournals.org/content/16/2/587.full
SO  - Mol Pharmacol1979 Sep 01; 16
AB  - The synaptosomal uptake of methadone was kinetically resolved into a diffusional and a saturable transport component. The latter process had an apparent Km and Vmax of 8.5 µM and 56.5 pmol/mg protein per 30 seconds, and led to synaptosomal accumulation of the drug. Lowering the temperature noncompetitively inhibited saturable transport which displayed a Q10 of 1.99. Incubation with 2,4-dinitrophenol had differential effects on methadone transport. While total uptake was slightly enhanced due to stimulation of the diffusional component, mediated transport was inhibited 93%. The pH dependence of uptake indicated that methadone was transported in its unionized form. The transport process was independent of sodium, lacked stereospecificity, and was insensitive to ouabain. In disrupted synaptosomes drug uptake was markedly diminished and the process lost its dependence on temperature and pH. Exodus of methadone from synaptosomes occurred rapidly, and reached equilibrium in 3 minutes. During efflux, counter-transport of methadone was demonstrated. Methadone efflux was also transaccelerated by desipramine, levorphanol and pentazocine. Furthermore, these drugs, but not biogenic amines and morphine, competitively inhibited synaptosomal uptake of methadone displaying Ki values between 8 and 24 µM. The findings characterize an active transport system for methadone in synaptosomes, and provide evidence for sharing of the transport carrier by several other drugs, structurally related to basic amines.