Abstract
The permeability of the blood-brain barrier (BBB) of rats to 3H-imipramine (IMP) and 3H-desipramine (DMI) was measured by a tissue-sampling 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 PSapp 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/Kd) of 3H-IMP to bovine serum albumin (BSA), human serum albumin (HSA) and α1-acid glycoprotein (α1-AGP) were 4.52, 1.48 and 57.89 mM-1, respectively, and that of 3H-DMI to α1-AGP was 38.92 mM-1. On the other hand, the in vivo n/Kd values of the binding of 3H-IMP to BSA, HSA and α1-AGP estimated from the single-injection experiment were 0.597, 0.754 and 14.73 mM-1, respectively, and that of 3H-DMI to α1-AGP was 5.90 mM-1. The in vitro n/Kd values of the binding of 3H-IMP and 3H-DMI to various serum proteins were thus larger than the corresponding in vivo n/Kd 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 α1-AGP by Pardridge et 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.
