Weak-acid hypothesis

Weak Acid" and "Intermediate-Diffusion" Hypotheses. Two hypotheses (which are not necessarily mutually exclusive) have been proposed for the entry and systemic mobility of chemicals in the phloem the "weak-acid" hypothesis proposed by Crisp and colleagues (5), and the "intermediate-diffusion" hypothesis proposed by Edgington and Peterson (4). These are illustrated in Figure 5. 

The weak-acid hypothesis proposes that compounds which have a free COOH group on the molecule will be in the protonated state in the apoplast because of the low pH of the apoplast (pH 5 to 5.5). 

There is qualified support for the weak-acid hypothesis, particularly for compounds such as 2,4-dichlorophenoxyacetic acid. Crisp and Look (.5) compared the phloem mobility of several synthetic 4-chlorophenoxy derivatives. The carboxyl derivative was loaded and transported in the phloem, whereas derivatives in which the COOH group was replaced by an ethyl ester, amide, ketone, alcohol, or amino group were not translocated. 

Although the weak acid hypothesis appears to explain the mobility of compounds such as chlorophenoxy derivatives, there are several exceptions to the weak-acid hypothesis (4, 1A> 15). For example, some xenobiotics are phloem mobile but are not weak acids and do not appear to be converted to a weak acid prior to transport (e.g., amitrole, oxamyl). Also, some xenobiotics (e.g., glyphosate) which have an ionizable COOH group are loaded into the phloem independently of apoplast pH. These should lose their mobility under pH conditions which ionize the chemical in the free space. Furthermore, accumulation of the weak acid glyphosate against a concentration gradient does not occur (14). 

The spirotetramat-enol 44 shows a noticeable water solubility and is a weak acid (pKa 4.9), rendering the compound mobile within the symplast (phloem) of the plant, according to the weak acid hypothesis [29]. Hence it can move acro-and basipetally, and even protects the roots when foliarly applied. 

STENSLAND With respect to the partial pressure of CO2, you can see with the aid of Fig. 1, that we need to have about 1600 ppm instead 320 ppm to achieve an ion balance. This high value would not be present in the laboratory. With respect to the weak acid hypothesis, such an anion could produce the required ion balance. Based on conductivity data, Granat dismissed the idea that an Important ion was missing. At this time, I do not have enough conductivity data to rule out this possibility. 

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],... 

For weak acids, e.g., salicylic acid, the dependency on a pH gradient becomes complex since both the passive diffusion and the active transport process will be dependent on the proton concentration in the apical solution [61, 63, 98, 105] and a lowering of the pH from 7.4 to 6.5 will increase the apical to basolateral transport more than 20-fold. Similarly, for weak bases such as alfentanil or cimetidine, a lowering of the pH to 6.5 will decrease the passive transport towards the basolateral side [105]. The transport of the ionizable compound will, due to the pH partition hypothesis, follow the pKa curve. 

Clearly a different model for understanding the removal process was in order. And the current hypothesis is that nitrogens are protonated at low pH values probably as well, even somewhat above the pH at which Octolig should not used. A workingh)rpothesis consistent with Figure 5 is that at least two important considerations are involved (1) The nitrogens must be protonated, and (2) species to be removed must be anions or if weak acids convertible to anions [39]. 

To sum up, for pyrrole the situation seems to be clearer in the sense that the conjugative effect overcomes the inductive, leading to a charge distribution similar to that of aniline. This hypothesis is confirmed by the fact that pyrrole itself is a weak acid and that the basic center is not the nitrogen atom but the a-carbon.42 For furan... 

Although the pH-partition hypothesis is useful, it must be viewed as an approximation because it does not adequately account for certain experimental observations. For example, most weak acids are well absorbed from the small intestine, which is contrary to the predictions of the pH-partition hypothesis. Similarly, quaternary ammonium compounds are ionized at all pHs but are readily absorbed from the gas... 

Lambert, R.J.W. and Bidlas, E. 2007. An investigation of the Gamma hypothesis A predictive modelling study of the effect of combined inhibitors (salt, pH and weak acids) on the growth of Aeromonas hydrophila. International Journal of Food Microbiology 115 12-28. 

An important conclusion has been arrived at by McBam and Kam (loc at) in a paper with the following self-explanatory title The effect of salts on the vapour pressure and degree of dissociation of acetic acid in solution An expenmental refutation of the hypothesis that neutral salts increase the dissociation constants of weak acids and bases ... 

Figure 4.6 Surface pH hypothesis for weak acids and bases. A model for the influence of the microclimate pH in rat proximal jejunum on weak electrolyte permeation. The weak acid A is converted to neutral by the presence of H+ in the microclimate. The undissociated form can easily be absorbed through the mucosa. In contrast, the weak base B is protonated by the H+ to BH+ which is less absorbed through the membrane.

A second type of behavior occurs for weak acids like HCN, H2S, and aromatic sulfonamides (ArS02NH2). Assuming that the anions (conjugated bases) bind the low-pH species of the enzyme, the bell-shaped plot of log K versus pH (Figure 2.15) can be accounted for. In fact, at low pH, the inhibitors are in the protonated form, which is not suitable for metal binding. At high pH the concentration of the low-pH species of the enzyme decreases. The maximal apparent affinity is experimentally halfway between the p/fa of the inhibitor and the p Ta of the enzyme, treated as if it were only one. The same type of curve is also expected if the high-pH species of the enzyme binds the weak acid. Indeed, kinetic measurements seem to favor this hypothesis for sulfonamides. ... 

The evidence of the importance of dissociation in drug absorption is found in the resuit of studies in which pH at the absorption site is changed (Tabies 9.1 and 9.2). Tabie 9.2 cieariy shows the decreased absorption of a weak acid at pH 8.0 compared to pH 1.0 (13). On the other hand, an increase to pH 8.0 promotes the absorption of a weak base with practicaiiy nothing absorbed at pH 1.0. The data in Tabie 9.2 aiso permits a comparison of intestinai absorption of acidic and basic drugs from buffered soiutions ranging from pH 4.0 to 8.0 (14). These resuits are in agreement with the pH-partition hypothesis. 

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