Brain Penetration

The work of Young et al. [1] provides a classic example of the role of increased H-bonding potential in preventing access to the CNS (crossing capillary and astrocyte cell membranes; Figure 4.2). In this example Alog P provided a measure of H-bond-ing potential.

Much of the data produced in studies such as this has measured the partitioning of drugs into whole brain from blood or plasma. The importance of lipophilicity in brain distribution has therefore been highlighted in many reviews [3,4], however the majority of these have concentrated on total drug concentrations which, given the lipid nature of brain tissue, over-emphasizes the accumulation of lipophilic drugs.

Whilst giving some ideas of the penetration into the brain, such data are limited in understanding the CNS activity of drugs. Whole brain partitioning actually repre-

Fig. 4.2 Penetration of antihistamine compounds into the CNS correlated with Dlog P (log Pcyclohexane - log P octanol ) as a measure of hydrogen bonding potential.

Fig. 4.2 Penetration of antihistamine compounds into the CNS correlated with Dlog P (log Pcyclohexane - log P octanol ) as a measure of hydrogen bonding potential.

sents partitioning into the lipid of the brain, and not actually access to drug receptors. For instance, desipramine partitions into brain and is distributed unevenly [5]. The distribution corresponds to lipid content of the brain regions and not to specific desipramine binding sites. Thus correlations such as those above describe the partitioning of the drug into lipid against the partitioning of the drug into model lipid. For receptors such as 7TMs ECF concentrations determine activity. The ECF can be considered as the aqueous phase of the CNS. CSF concentrations can be taken as a reasonable guide of ECF concentrations. The apparent dramatic differences in brain distribution described for total brain, as shown above (three to four orders of magnitude), collapse to a small ratio when the free (unbound) concentration of drug in plasma is compared to the CSF concentration. Whole brain/blood partitioning reflects nothing but an inert partitioning process of drug into lipid material.

The lack of information conveyed by total brain concentration is indicated by studies on KA-672 [6], a lipophilic benzopyranone acetylcholinestrase inhibitor. The compound achieved total brain concentrations of 0.39 |M at a dose of 1 mg kg-1 equivalent to the IC50 determined in vitro (0.36 |M). Doses up to 10 mg kg-1 were without pharmacological effect. Analysis of CSF indicated concentrations of the compound were below 0.01 |M readily explaining the lack of activity. These low concentrations are presumably due to high (unbound) free drug clearance and resultant low concentrations of free drug in the plasma (and CSF).

Free unbound drug partitioning actually reflects the fact that the drug is reaching the receptor and is having a pharmacological effect. Unless active transport systems are invoked the maximum CSF to plasma partition coefficient is 1. This should be contrasted to the 100- or 1000-fold affinity of total brain compared to blood or plasma. The minimum partitioning based on a limited data set appears to be 0.1. Figure 4.3 compares lipophilicity (log D) in a series of diverse compounds that illustrate the limited range of partitioning. It should be noted that the term log D is not a perfect descriptor and some of the measures which incorporate size and hydrogen bonding may be better. Clearly though, the CNS is more permeable than imagined, allowing drugs such as sulpiride (Figure 4.3) to be used for CNS applications.

Fig. 4.3 CSF concentration/free (unbound) plasma concentration ratios for neutral and basic drugs: 1, ritropirronium; 2, atenolol; 3, sulpiride; 4, morphine; 5, cimetidine; 6, meto-prolol; 7, atropine; 8, tacrine; 9, digoxin; 10, propranolol; 11, carbamazepine; 12, ondansetron; 13, diazepam; 14, imipramine; 15, digitonin; 16, chlorpromazine and acidic drugs, a, salicylic acid; b, ketoprofen; c, oxyphenbutazone and d, indomethacin compared to log D.

Fig. 4.3 CSF concentration/free (unbound) plasma concentration ratios for neutral and basic drugs: 1, ritropirronium; 2, atenolol; 3, sulpiride; 4, morphine; 5, cimetidine; 6, meto-prolol; 7, atropine; 8, tacrine; 9, digoxin; 10, propranolol; 11, carbamazepine; 12, ondansetron; 13, diazepam; 14, imipramine; 15, digitonin; 16, chlorpromazine and acidic drugs, a, salicylic acid; b, ketoprofen; c, oxyphenbutazone and d, indomethacin compared to log D.

The use of microdialysis has enabled unbound drug concentrations to be determined in ECF, providing another measurement of penetration across the blood-brain barrier and one more closely related to activity. A review of data obtained by microdialysis [7], showed that free drug exposure in the brain is equal to or less than free drug concentration in plasma or blood, with ratios ranging from 4% for the most polar compound (atenolol) to unity for lipophilic compounds (e.g. carbamazepine). This largely supports the similar conclusions from the CSF data shown above. This relationship is illustrated in Figure 4.4.

Somewhat surprisingly, microdialysis has also revealed that the time to maximum concentration (Tmax) within the CNS is close to the Tmax value in blood or plasma, irrespective of lipophilicity. For example, the CNS Tmax for atenolol (log D74 = - 1.8) occurs at 2 min in the rat after intravenous administration [8]. In addition the rate of elimination (half-life) of atenolol and other polar agents from the CNS is similar to that in plasma or blood. The implication of these data is that poorly permeable drugs do not take longer to reach equilibrium with CNS tissue than more lipophilic agents

Fig. 4.4 Relationship between lipophilicity and CNS penetration expressed as free drug AUC ratio in brain to blood (data from reference [16]).

4.3 Volume of Distribution and Duration | 51

as might be assumed. To explain these observations, it has been postulated that nonpassive transport (i.e. active) processes play a role in determining CNS exposure [7].

The fact that hydrophilic compounds have ready access to the CNS, albeit up to 10fold lower than lipophilic compounds, is not generally appreciated. In the design of drugs selectivity over the CNS effects has sometimes relied on making compound hydrophilic. Clearly this will give some selectivity (up to 10-fold), although this may not be sufficient. For instance p-adrenoceptor antagonists are known to cause sleep disorders. In four drugs studied the effects were lowest with atenolol (log D = - 1.6), intermediate with metoprolol (log D = - 0.1), and highest with pindolol (log D = - 0.1) and propranolol (log D = 1.2). This was correlated with the total amount present in brain tissue [9], which related to the log D values. Further analysis of this data [10] using CSF data and receptor affinity to calculate receptor occupancy, demonstrated that there was high occupation of the p1 central receptor for all drugs. Propranolol showed a low occupancy, possibly because the active 4-hydroxy metabolite is not included in the calculation. In contrast, occupation of the p2 central receptor correlated well with sleep disturbances. The incidence of sleep disturbances is therefore not about penetration into the CNS but the p1/p2 selectivity of the compounds (atenolol > metoprolol > pindolol = propranolol). The relative receptor occupancies are illustrated in Figure 4.5.

Fig. 4.5 Central receptor occupancy after oral administration of p-adrenoceptor antagonists: A, atenolol; B, metoprolol; C, pindolol; D, propranolol. The high occupancy of p1 receptors does not correlate with physicochemical properties (lipophilicity). The occupation of p2 receptors correlates with sleep disturbances and the intrinsic selectivity of the compounds.

For a small drug molecule, penetration into the target may often be easier to achieve than duration of action. Assuming duration of action is linked to drug halflife, then distribution as outlined below can be an important factor.

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