Methadone binding to orosomucoid (α1-acid glycoprotein): Determinant of free fraction in plasma

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°. In plasma samples from 29 healthy subjects free fraction of dl-methadone was (x% ± SD) 10.62 ± 1.43. There were significant variations among subjects (p < 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 α1-acid glycoprotein (α1-AGP), an acute-phase reactant protein. Percentage dl-methadone bound to purified human serum albumin (HSA) (4.1 gm/dl) was 36.60% (x ± SD). Isolated α1-AGP bound dl-methadone more avidly. As the α1-AGP increased from 0.05 to 2.0 gm/l, free fraction fell from 92.40% to 8.80%. Addition of α1-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 α1-AGP. Elevations of α1-AGP that occur in a variety of diseases may alter the kinetic and pharmacologic activity of methadone. Clinical Pharmacology and Therapeutics (1981) 29, 211–217; doi:10.1038/clpt.1981.34