Brain/plasma ratio

In addition to the data generated from plasma samples in a standard PK study, for targets that are contained within the brain, it is also important to determine brain levels of compound, so that brain/plasma ratios can be determined. Again, these data should be correlated with in vitro assays and calculated properties such as BBB PAMPA [39]... 

Tryptamines that are unsubstituted on the terminal amine are good substrates for oxidative deamination by MAO. Furthermore, it has been demonstrated that tryptamine and 5-methoxytryptamine cross the blood-brain barrier with great difficulty administration of 50 mg/kg 5-methoxytryptamine to rats results in a low brain/plasma ratio when measured 15 min postadministration (242). 

There has been a major advance in our understanding of drug exposure in the CNS as detailed in the seminal paper of Kalvass and Maurer and in follow-up publications (vide supra) [9,12,13]. This work emphasizes the importance of unbound drug in the brain, and its relationship to unbound drug in the plasma and brain/plasma ratio. One expects that this work should have a major impact on how CNS drugs are optimized and evaluated. There appears to be little... 

Burns and Weaver [6] developed an MLR-based BBB permeability model using two experimental measures of BBB penetrability (brain/plasma ratio and the brain-uptake index) and 14 theoretically derived biophysical predictors based on Stein s hydrogen-bonding number and Randic s topological properties of the molecules. The final model accurately predicted the ability of test molecules to cross the BBB. 

FIGURE 28.3 Effect of Pluronic P85 on the digoxin brain/plasma ratio in the wild-type mice when compared to the mdr la/b (—/—) knockout mouse at 5 h postdose. A tracer dose of [3H]-digoxin (4 p,Ci 7.8 gg/kg) in PBS control or 1% Pluronic P85 solution (100 xL) was administered intravenously into wild-type control group or Pgp knockout mice. Four hours following injection animals were sacrificed and the amount of digoxin in the blood in the brain was assayed. (From Batrakova, E., et al. J. Pharmacol. Exp. Ther., 296, 551, 2001. With permission.)... 

Prediction of Free Brain/Plasma Ratio In Vitro... 

A summary of properties for indirubin-3 -monoxime is given in Table 6. The molecule is flat, has a moderate logD and acidic character which leads to acceptable predicted solubility. Although the number of H-bond donor groups is quite large (n = 3), it is likely that a tautomeric form in which the hydroxy indole is intramolecularly bonded to the indole nitrogen would be favoured and, if so, this would lead to improved permeability and less desolvation penalty. The PSA is moderate (74 A ) and the predicted brain-plasma ratio [82] is 0.3 (likely... 

Name Brain-plasma ratio Likely range... 

---