Methadone binding to orosomucoid (α 1 ‐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 (x̄% ± 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 α 1 ‐acid glycoprotein (α 1 ‐AGP), an acute‐phase reactant protein. Percentage dl ‐methadone bound to purified human serum albumin (HSA) (4.1 gm/dl) was 36.60% (x̄ ± SD). Isolated α 1 ‐AGP bound dl ‐methadone more avidly. As the α 1 ‐AGP increased from 0.05 to 2.0 gm/l, free fraction fell from 92.40% to 8.80%. Addition of α 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 α 1 ‐AGP. Elevations of α 1 ‐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