Effects of Albumin and α_1-Acid Glycoprotein on the Transport of Imipramine and Desipramine through the Blood-Brain Barrier in Rats(Pharmaceutical)

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The permeability of the blood-brain barrier (BBB) of rats to ^3H-imipramine (IMP) and ^3H-desipramine (DMI) was measured by a tissue-sampiing single-injection technique to examine the protein mediated transport. Increased concentrations of serum proteins added to the carotid injection solution resulted in decreases in the brain extraction and PS_<app> of ^3H-IMP and ^3H-DMI, The extraction ratio of ^3H-IMP (0.92) was higher than that of ^3H-DMI(0.24) in the case of the buffer injection solution. The values of in vitro binding activity (n/K_d) of ^3H-IMP to bovine serum albumin (BSA), human serum albumin (HSA) and α_1-acid glycoprotein (α_1-AGP) were 4.52, 1.48 and 57.89 mM^<-1>, respectively, and that of ^3H-DMI to α_1-AGP was 38.92mM^<-1>. On the other hand, the in vivo n/K_d values of the binding of ^3H-IMP to BSA, HSA and α_1-AGP estimated from the single-injection experiment were 0.597, 0.754 and 14.73 mM^<-1>, respectively, and that of ^3H-DMI to α_1-AGP was 5.90 mM^<-1>. The in vitro n/K_d values of the binding of ^3H-IMP and ^3H-DMI to various serum proteins were thus larger than the corresponding in vivo n/K_d Values. A marked difference was found between the observed extraction ratios and what would be predicted if only the unbound ^3H-IMP or ^3H-DMI is transported, although the difference was not large in the case of HSA. These results suggest that protein mediated transport, previously found for propranolol and lidocaine with α_1-AGP by Pardridge el al. (J. Clin. Invest., 71,900 (1983)), also operates for ^3H-IMP and ^3H-DMI, and this phenomenon seems to be independent of both the species and the source of serum protein, at least for ^3H-IMP. Further, the brain extraction ratio of ^3H-DMI was much lower than that of the parent drug ^3H-IMP, probably due to their different degrees of lipophilicity.
公益社団法人日本薬学会の論文
1987-01-25

Effects of Albumin and α_1-Acid Glycoprotein on the Transport of Imipramine and Desipramine through the Blood-Brain Barrier in Rats(Pharmaceutical)

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