Stereoselective binding of the enantiomers of four closely related N-methyl-barbiturates to human, bovine, and rat serum albumin.
Albumin binding for the enantiomers of four closely related N-methyl-5-phenyl-5-alkyl-barbiturates 1-4 was investigated for three different mammalian species by means of equilibrium dialysis. Lipid solubility (n-heptane/phosphate buffer distribution coefficient) increased stepwise by a factor of 56 from 1 to 4. Bovine serum albumin: The (S)-(+)-enantiomers of 1-4 were bound in a higher percentage than the (R)-(-)-enantiomers; lengthening of the aliphatic side-chain increased the binding extent in both enantiomeric groups. Human serum albumin: Binding of (S)-(+)-1 and (S)-(+)-4 was higher than that of the (R)-(-)-enantiomers; with (S)-(+)-2 and (S)-(+)-3 it was much lower than that of the corresponding (R)-(-)-enantiomers. Lengthening of the aliphatic side chain increased the binding extent of the (S)-(+)- as well as the (R)-(-)-enantiomers, but with two exceptions: 1. The (S)-(+)-1 binding exceeded that of the (S)-(+)-2 by a factor of nearly two. 2. The binding extent of (R)-(-)-4 was not further increased in comparison to (R)-(-)-3. Rat serum albumin: (S)-(+)-1 and (S)-(+)-2 were bound in a lower percentage than the (R)-(-)-enantiomers, both 3-enantiomers showing an equal binding extent; (S)-(+)-4 was bound to a slightly greater extent than the (R)-(-)-4. In the group of the (S)-(+)-enantiomers, the binding extent increased from 1 to 4, whereas in that of the (R)-(-)-enantiomers only between 1 and 4. Structural differences between the serum albumins of three mammalian species possibly cause the enantioselective binding pattern found for the enantiomers of 1-4, and are responsible for the finding that the binding extent in some cases did not correlate with the lipid solubility of the compounds.
Department of Pharmacology and Toxicology, University of the Saarland, Homburg, Germany.
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Büch
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Krug
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Knabe
D000818:Animals; D001463:Barbiturates / Q000378:metabolism*; D002417:Cattle; D006801:Humans; D011485:Protein Binding; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism*; D012995:Solubility; D013237:Stereoisomerism
D001463:Barbiturates; D012709:Serum Albumin