Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha 1-acid glycoprotein.
The plasma concentrations of alpha 1-acid glycoprotein (AAG), albumin, triglycerides, cholesterol, and total proteins, as well as the plasma binding of racemic, d-methadone, and l-methadone were measured in 45 healthy subjects. The AAG phenotypes and the concentrations of AAG variants were also determined. The measured free fractions for racemic, d-methadone, and l-methadone were, respectively, 12.7% +/- 3.3%, 10.0% +/- 2.9%, and 14.2% +/- 3.2% (mean +/- SD). A significant correlation was obtained between the binding ratio (B/F) for dl-methadone and the total AAG concentration (r = 0.724; p less than 0.001). A multiple stepwise regression analysis showed that AAG was the main explanatory variable for the binding of the racemate. When concentrations of AAG variants were considered, a significant correlation was obtained between the binding ratio of dl-methadone and orosomucoid2 A concentration (r = 0.715; p less than 0.001), a weak correlation between dl-methadone and orosomucoid1 S concentration (r = 0.494; p less than 0.001), and no correlation between dl-methadone and orosomucoid1 F1 concentration (r = 0.049; not significant). Similar findings were obtained with the enantiomers. This study shows the importance of considering not only total AAG but also concentrations of AAG variants when measuring the binding of methadone and possibly of other drugs in plasma.
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Department of Adult Psychiatry, University of Lausanne, Hôpital de Cery, Prilly-Lausanne, Switzerland.
Cuendet
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Baumann
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D000328:Adult; D001798:Blood Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008691:Methadone / Q000378:metabolism*; D008875:Middle Aged; D009961:Orosomucoid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D011485:Protein Binding; D012044:Regression Analysis; D012709:Serum Albumin / Q000378:metabolism; D013237:Stereoisomerism; D014280:Triglycerides / Q000097:blood
D001798:Blood Proteins; D009961:Orosomucoid; D012709:Serum Albumin; D014280:Triglycerides; D002784:Cholesterol; D008691:Methadone