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

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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.degree. C. In plasma samples from 29 healthy subjects, free fraction of dl-methadone was (.hivin.x[mean]% .+-. 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 .alpha.1-acid glycoprotein (.alpha.1-AGP).sbd.an acute-phase reactant protein. Percentage dl-methadone bound to purified human serum albumin (HSA) (4.1 g/dl) was 36.60% (.hivin.x .+-. SD). Isolated .alpha.1-AGP bound dl-methadone more avidly. As the .alpha.1-AGP increased from 0.05-2.0 g/l, free fraction fell from 92.40-8.80%. Addition of .alpha.1-AGP (0.05-2.0 gm/l) to a physiologic concentration of purified HSA, or to whole plasma progressively increased methadone binding. In 8 monozygotic twin pairs, within-pair differences in binding of dl-methadone were less than in 8 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.