The pH partition hypothesis

For any given drug (or, for that matter, for any biological membrane) there must exist an optimal value of partition coefficient for transport of drug across the membrane. This value is called P0. 

The situation becomes (even) more complicated if the drug ionises at the pH of the body compartment. For weak acids and weak bases, the aqueous and lipid solubility of the compound will depend on the extent to which the drug is ionised, which in turn will depend on the pK3 of the acidic and basic groups involved and the pH of the surroundings. 

What all this means in practice is that drugs are absorbed quite effectively from the small intestine even if they exist in a predominantly ionised form. The absorption process obeys the law of mass action, which was introduced in Chapter 1. This law is fundamentally an equilibrium process, and, as with any equilibrium, rapid removal of the products or compounds on the right-hand side of the equilibrium arrow will shift the equilibrium in that direction. This is exactly what happens in drug absorption across the gut membrane a small amount of unionised drug is absorbed by passive diffusion and whisked away by the rich blood supply of 

Some ionised drug molecules can traverse the lipophilic gut membrane by combining with an ion of opposite charge (a counter ion) to form an ion pair. The ion pair, although composed of two ionic species, behaves as a neutral molecule with a high partition coefficient and can cross biomembranes effectively Quaternary ammonium compounds, which are charged at all values of pH, may be absorbed into the body in this way  

Most of the gastrointestinal absorption studies were found to be in accord with the principles of the pH-partition hypothesis. However, several deviations were noted and attributed to the unstirred water layer, the microclimate pH, and the mucus coat adjacent to the epithelial cell surface [150-152], 

Although the pH-partition hypothesis relies on a quasi-equilibrium transport model of oral drug absorption and provides only qualitative aspects of absorption, the mathematics of passive transport assuming steady diffusion of the un-ionized species across the membrane allows quantitative permeability comparisons among solutes. As discussed in Chapter 2, (2.19) describes the rate of transport under sink conditions as a function of the permeability P, the surface area A of the membrane, and the drug concentration c (t) bathing the membrane  

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Absorption, the Henderson-Hasselbalch Equation and the pH-partition Hypothesis... 

The pH-partition hypothesis, now widely accepted in pharmaceutical research, suggests that membrane permeability will be highest at the pH where the molecule is least charged however, this is also the pH where the molecule is least soluble. (In Brodie s work, the compounds tested have relatively high water solu-... 

Thomae, A. V., Wunderli-Allenspach, H., Kramer, S. D. Permeation of aromatic carboxylic adds across lipid bilayers the pH-partition hypothesis revisited. Biophys. J. 2005, 89,1802-1811. 

As mentioned previously, pH will also influence the absorption of an ionizable drug once it is in solution, as outlined in the pH partition hypothesis. Most drugs, however, are best absorbed from the small intestine regardless of pKa and pH. In some instances, especially lower down the GIT, there is the possibility of in-... 

PERMEABILITY-SOLUBILITY-CHARGE STATE AND THE pH PARTITION HYPOTHESIS... 

The absorption of short-chain weak acids in the rat intestine, as a function of pH, does not appear to conform to the pH partition hypothesis [44]. Similar anomalies were found with weak bases [77]. The apparent pKa values observed in the absorp-tion-pH curve were shifted to higher values for acids and to lower values for bases, compared with the true pKa values. Such deviations could be explained by the effect of an acid layer on the apical side of cells, the so-called acid pH microclimate [44,70,73,76-84],... 

Figures 4.2b, 4.3b, and 4.4b are log-log speciation plots, indicating the concentrations of species in units of the total aqueous sample concentration. (Similar plots were described by Scherrer [280].) The uppermost curve in Fig. 4.2b shows the concentration of the uncharged species in octanol, as a function of pH. If only uncharged species permeate across lipid membranes, as the pH-partition hypothesis...

The effective permeability of ionizable molecules depends on pH, and the shapes of the permeability-pH profiles can be theoretically predicted when the pKa of the molecule is known, the pH partition hypothesis are valid, and the resistance of... 

For ionizable sample molecules, it is possible to create an effective sink condition in PAMPA by selecting buffers of different pH in the donor and acceptor compartments. For example, consider salicylic acid (v>Ka 2.88 see Table 3.1). According to the pH partition hypothesis, only the free acid is expected to permeate lipophilic membranes. If the donor pH < 2 and the acceptor pH is 7.4, then as soon as the free acid reaches the acceptor compartment, the molecule ionizes, and the concentration of the free acid becomes effectively zero, even though the total concentration of the species in the acceptor compartment may be relatively high. This situation may be called an ionization-maintained sink. 

Palm et al. [578] derived a two-way flux equation which is equivalent to Eq. (7.13), and applied it to the permeability assessment of alfentanil and cimeti-dine, two drugs that may be transported by passive diffusion, in part, as charged species. We will discuss this apparent violation of the pH partition hypothesis (Section 7.7.7.1). 

Intrinsic Permeability, Permeability-pH Profiles, Unstirred Water Layers (UWL), and the pH Partition Hypothesis... 

Figure 7.45 Molecules that may violate the pH partition hypothesis.

It is difficult to prove that quaternary ammonium compounds can cross lipid bilayers using cell uptake experiments, since several mechanisms may be operative, and separating contributions from each may be very difficult [1]. It may be an advantage to use PAMPA to investigate transport properties of permanently ionized molecules. Of all the molecules whose permeabilities were measured under iso-pH conditions in 2% DOPC/dodecane, verapamil, propranolol, and especially quinine seem to partially violate the pH partition hypothesis, as shown in Figs. 7.47a-c. In Fig. 7.47c, the solid line with slope of +1 indicates the expected effective permeability if the pH partition hypothesis were strictly adhered to. As can be seen at pH 4... 

Figure 7.47 Examples of three bases that appear to violate the pH partition hypothesis in 2% DOPC/dodecane PAMPA models (a) verapamil (pKa 9.07) (b) propranolol (c) guinine (pKa 8.55, 4.24).

For convenience, these qualitative and quantitative absorption models have been classified into three categories based on their dependence on spatial and temporal variables [2], The first category is referred to as quasi-equilibrium models. The quasi-equilibrium model, including the pH-partition hypothesis... 

The majority of evidence supporting the pH-partition hypothesis is from studies of gastrointestinal absorption, renal excretion, and gastric secretion of drugs [11]. While correlation between absorption rate and pKa was found to be consistent with the pH-partition hypothesis, deviations from this hypothesis were often reported [12]. Such deviations were explained by the existence of a mucosal unstirred layer [13,14] and/or a microclimate pH [15]. 

The un-ionized form is assumed to be sufficiently lipophilic to traverse membranes in the pH-partition hypothesis. If it were not, no transfer could be predicted, irrespective of pH. The lipophilicity of compounds is experimentally determined as the partition coefficient (log P) or distribution coefficient (log D) [16]. The partition coefficient is the ratio of concentrations of the neutral species between aqueous and nonpolar phases, while the distribution coefficient is the ratio of all species between aqueous and nonpolar phases [17,18],... 

In reviewing the pH-partition hypothesis, it is apparent that it is an oversimplification of a very complex process. It does not consider one of the critical physicochemical factors, solubility. Low aqueous solubility is often the cause of the low bioavailability. To address this issue, Dressman et al. [28] developed an absorption potential concept that takes into account not only the partition coefficient but also solubility and dose. Using a dimensional analysis approach, the following simple equation was proposed ... 

Although the pH-partition hypothesis and the absorption potential concept are useful indicators of oral drug absorption, physiologically based quantitative approaches need to be developed to estimate the fraction of dose absorbed in humans. We can reasonably assume that a direct measure of tissue permeability, either in situ or in vitro, will be more likely to yield successful predictions of drug absorption. Amidon et al. [30] developed a simplified film model to correlate the extent of absorption with membrane permeability. Sinko et al. [31] extended this approach by including the effect of solubility and proposed a macroscopic mass balance approach. That approach was then further extended to include facili-... 

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