Log Papp values

A close inspection of the Caco-2 data in Fig. 4.9a suggests a hyperbolic relationship, with log Papp values leveling off at about —5. Similar log Papp curve shapes have been observed elsewhere [41], and are thought to arise as a consequence of the unstirred water layer phenomenon. 

There is good permeation potential (log Papp value > -5.0 desirable). 

Similar conclusions could be derived from an investigation of antihypertensive clonidine analogs, with respect to their peripheral hypertensive side effects. For a series of clonidine-related imidazolines, log Papp values were determined in -octanol/buffer at pH 7.4, central antihypertensive activities C2s (molar doses that cause a 25% blood pressure decrease, intravenous application) in anesthesized rats, peripheral hypertensive activities C o (molar doses that cause a 60-mm Hg blood pressure increase, intravenous application) in pithed rats (i.e., rats without central nervous system control), binding affinities IC50ai to ai receptors (replacement of prazosin), and binding affinities IC50+ 10 a2 receptors (replacement of clonidine) [86,87],... 

The concentrations of A and in the organic pha may be neglected for compounds which are not too lipophilic much simpler equations than eqs. 105 and 106 can be used to estimate the log Papp values of most acids (eq. 107) and bases (eq. 108) at pH values which are not too far from the pKa values. 

A better and more consistent result is obtained if log k bs values are calculated from % ABS values by appropriate transformation and if log Papp values and the parabolic [469] or the bilinear model are used, e.g. eq. 110 [442]. 

Eq. Ill [345] correlates the buccal absorption rate constants of an acid (p-hexylphenylacetic acid, pK = 4.36) and a base (propranolol, pK = 9.45) at different pH values with log Papp values (Table 16) [345, 470]. 

The use of log Papp values is appropriate in all cases where rate constants are involved, but not for binding or other equilibrium systems [173], The correct approach to equilibrium systems is demonstrated by eq. 112 (Kj = inhibition of monoamine oxidase by amines and alcohols I = 0 for amines, I = 1 for alcohols), where the biological data have been corrected for the concentration of the unionized form (Table 17) [175]. 

For the same class of compounds Timmermans determined log Papp values (n-octanol/buffer, pH = 7.4), binding affinities to oti adrenoceptors, ICsoOti (displacement of the oti antagonist prazosin), binding affinities to a2 adrenoceptors, IC5(,a2 (displacement of the 2 agonist clonidine), antihypertensive activities (mediated by a central mechanism) in anesthetized normotensive rats (ED2s%, i v. application), and hypertensive activities (mediated by peripheral a stimulation which, in the absence of central nervous system regulation, causes blood vessel contraction) in... 

Figure 9.2 Relationship between log P values of various drugs and Papp across the passage-cultured human nasal epithelial cell monolayer using LCC method.

Detailed in vivo studies on the tissue distribution in rabbits of a set of 10 drugs have been reported together with their partition coefficients, Kp, in various tissues and partition coefficients log Papp in four solvent systems octanol, benzene, chloroform, and triolein [91]. The results are summarized in Table 4.26. The Kp values in the studied tissues, including bones, showed a large variation in ranking and a significant variation from tissue to tissue. It was found that the tissue-to-plasma partition coefficient of the non-ionized form of the dmgs, Kf,(w correlates best with log Poet. of the non-ionized form. 

Table 9.2 shows some permeation values (in cm s ) of sample drugs a value of log Papp <—5.0 indicates poor diffusion (less than 10 5 cm s ) through the membrane, and a value of log Papp >—5.0 describes good permeation. 

The dissociation equilibrium depends on the pH value of the aqueous phase and on the pA a value of the organic compound. Equation (34) (for acids) and Eq. (35) (for bases) describe the apparent partition coefficients log Papp of acids and bases at different pH values of the aqueous phase in an -octanol/buffer system ( Pu = partition coefficient of the neutral, uncharged form P = partition coefficient of the ionized,... 

Equations (34) and (35) describe sigmoidal curves with apparent partition coefficients log Papp = log Pu at pH < pATa (acids) and pH > pK (bases), and apparent partition coefficients log Papp - log P at pH3>pATa (acids) and pHwith constant Papp values for the neutral forms and steadily decreasing Papp values with increasing ionization, at pH > pKa for acids and pH < pATa for bases. 

This model is wrong for two reasons. Log % absorption values are used instead of rate constants, and differences p fa—pH are used to model the p7+, /p EI dependence of the colonic absorption (valid only if pH < pK ). The correct p/+/pl I correction procedure was applied by Scherrer and Howard [74] (Eq. (39)). They performed a nonlinear transformation of the percentage values (log %ABS) to absorption rate constants (log fcabs) and converted the log P values into log D values (distribution values between -octanol and an aqueous buffer of a certain pH value, nowadays most often called log Papp) by Eqs. (36) and (37) ... 

Much more complex models correlate the buccal absorption rate constants of these acids at different pH values, e.g. eq. 165 [479]. Even the rate constants for acidic and basic drugs can be combined to obtain one equation by using log Papp instead of log P (eq. Ill, chapter 4.5). 

If the true pfCj of the molecule is known, then a simple inspection of the plot of log Pe (or Papp in the case of cellular assays) versus pH can often reveal the values of both log Po and log Pabl-... 

For acids, at pH values well below their pKia value, for all intents and purposes Papp = P, since ionisation is suppressed and we are dealing with only the un-ionised form of the species. At pH values above the pKa, the value of Papp decreases because the species is ionising and moving into the aqueous layer. This approximate relationship is very simple and allows us to predict the distribution of the dmg at all pH values, provided that we know pKia and log P, for any given compound. The same applies to bases as discussed in Chapter 3. 

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