The chapter starts by describing what is meant by ‘brain uptake’ and will then focus on two quantitative measurements, (a) blood-brain distribution, and (b) brain perfusion. It is shown that there are no satisfactory ‘experimental models’ for either of these processes, and hence the need for in silico models. For blood-brain distribution, numerous in silico models have been proposed. The chapter will concentrate on those models for which a predictive assessment through independent test sets has been made, and which are capable of being implemented reasonably easily. There are several models in this category all of which can predict blood-brain distribution, as logBB, to about 0.4 log units, probably not far from the experimental error. Of course, such predictions are for passive transport only, and do not take into account active transport or efflux mechanisms.

The second quantitative measurement is brain perfusion that has replaced methods such as the Brain Uptake Index. Brain perfusion can be carried out using an injection of a bolus of a drug in blood, plasma, or saline, all at pH 7.4. Most recent work has used saline as the vehicle, but the number of published observations is relatively small, as compared to blood-brain distribution. Two recent papers that use perfusion from saline in order to construct in silico models will be discussed.

The effects of ionization of proton acids and bases will then be considered. It appears that for blood-brain distribution, no correction for ionization at pH 7.4 is needed (one or two models have an indicator variable for proton acids, but this is not very significant). On the other hand, in perfusion from saline at pH 7.4 it seems that some correction is needed, although the magnitude of the correction is not clear. Unless the problem of strong proton acids and strong proton bases can be solved, it will be difficult to construct general in silico models for brain perfusion from saline. In addition, the usual caveats over active transport and efflux mechanisms apply.

Finally, brain uptake as classified as CNS+ and CNS- is briefly considered.