title: Methadone binding to orosomucoid (alpha 1-acid glycoprotein): determinant of free fraction in plasma.
abstract: The distribution of basic drugs in blood differs qualitatively from that of acidic drugs. The binding of racemic, d-methadone, and l-methadone to human plasma and isolated protein fractions was studied by equilibrium dialysis at 37 degrees. In plasma samples from 29 healthy subjects free fraction of dl-methadone was (mean% +/- SD) 10.62 +/- 1.43. There were significant variations among subjects (p less than 0.001). The free fraction of the d-isomer was 9.24 +/- 1.61% and of the l-isomer, 12.44 +/- 1.53%. Plasma albumin concentration and degree of binding do not correlate, but in normal hypoalbuminemic subjects the free fraction of dl-methadone correlates negatively with the concentration of alpha 1-acid glycoprotein (alpha 1-AGP), an acute-phase reactant protein. Percentage dl-methadone bound to purified human serum albumin (HSA) (4.1 mg/dl) was 36.60% (mean +/- SD). Isolated alpha 1-AGP bound dl-methadone more avidly. As the alpha 1-AGP increased from 0.05 to 2.0 gm/l, free fraction fell from 92.40% to 8.80%. Addition of alpha 1-AGP (0.05 to 2.0 gm/l) to a physiologic concentration of purified HSA or to whole plasma progressively increased methadone binding. In eight monozygotic twin pairs, within-pair differences in binding of dl-methadone were less than in eight dizygotic twin pairs. Less than 20% of naloxone, codeine, morphine, heroin, pentazocine, and diphenoxylate bound to alpha 1-AGP. Elevations of alpha 1-AGP that occur in a variety of diseases may alter the kinetic and pharmacologic activity of methadone.
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008691:Methadone / Q000378:metabolism*; D008875:Middle Aged; D009961:Orosomucoid / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding; D014427:Twins
chemical_list: D008074:Lipoproteins; D009961:Orosomucoid; D008691:Methadone