PH partition theory

It was assumed for a long time that molecules can only cross a membrane in their neutral form. This dogma, based on the pH-partition theory, has been challenged [42, 43]. Using cyclic voltammetry it was demonstrated that compounds in their ionized form pass into organic phases and might well cross membranes in this ionized form [44]. 

The pH-partition theory or nonionic permeability hypothesis was first described by Jacobs in 1940 [66]. According to this concept, only neutral, preferably nonpolar compounds are able to cross biological membranes. The transcellular permeability pH-profile is then essentially characterized by the membrane partition coefficient and the pKa of the compound. The simplest quantitative description of membrane permeation is given by ... 

One of the original concepts governing oral absorption of organic molecules is the pH partition hypothesis . This hypothesis states that only the nonionized form of the drug is able to permeate the membranes of epithelial cells lining the GI tract [26], According to the classical pH-partition theory, permeability is expected to correlate not with the intrinsic partition coefficient but with the so-called distribution coefficient D of the solute [27], where D is defined as ... 

Generally, to produce a biological response, a drug molecule must first cross at least one biological membrane. The biological membrane acts as a lipid barrier to most drugs and permits the absorption of lipid-soluble substances by passive diffusion while lipid-insoluble substances can diffuse if at all across the barrier only with considerable difficulty. The interrelationship of the dissociation constant, lipid solubility, and pH at the absorption site and absorption characteristics of various drugs are the basis of the pH-partition theory. 

The major pathway of drug transport across buccal mucosa seems to follow simple Fickian diffusion [17]. Passive diffusion occurs in accordance with the pH-partition theory. Considerable evidence also exists in the literature regarding the presence of carrier-mediated transport in the buccal mucosa [18,19]. Examination of Eq. (1) for drug flux,... 

Passive Transcellular Pathway pH Partition Theory as the Basis of Understanding Membrane Permeability... 

These conditions are embodied in the pH-partition theory only nonionized lipid-soluble compounds will be absorbed by passive diffusion down a concentration gradient. Let us examine the three conditions in turn. 

Passive diffusion (lipid-soluble, noncharged molecules concentration gradient first order pH partition theory)... 

The interrelationship between the dissociation constant and lipid solubility of a drag, as well as the pH at the absorption site, is known as the pH-partition theory of drag absorption. Accordingly, rapid transcellular passive diffusion of a drag molecule may be due to ... 

Amoxicillin is well absorbed when given orally, with a bioavailability that appears to be much higher than expected in the light of its physico-chemical properties and the pH partition theory [191], Numerous studies show recovery of intact amoxicillin in urine after oral administration in the range 43 to 80 % after 6 to 8 hours, with most figures in the upper part of this range [147,171,172,187,188,190]. An additional 10 to 25 % of the dose appears in urine as the penicilloic acid [147,148,152,171,172,187] with a ratio of about 2 to 1 of the 5R to 5S isomers [152,171,172]. Amoxicillin is extensively distributed in body tissues and fluids, with adequate levels for antibacterial activity in most of them [187,188,190], The half life in serum is about one hour and is the same for oral, intramuscular and intravenous administration [187,188,190]. Co-administration with potassium clavulanate does not affect the absorption, distribution and excretion of amoxicillin [190]. 

Biomimetic artificiai membranes-factors Effects of pH and co-solvents on the BAMPA were investigated to determine the optimal conditions for the prediction of oral absorption. The permeability (Pam) of 33 structurally diverse drugs to the PC/PE/ PS/PI/CHO/1,7-octadiene membrane system [bio-mimetic lipid (BML) membrane] was measured at pH 5.5,6.5, and 7.4. The pH dependence of Pam was in accordance with the pH partition theory. The better prediction of oral absorption (fraction of a dose absorbed) was shown under the pH 5.5 condition for determining the permeability of poorly soluble compounds were examined. Dimethysulfoxide (DMSO), ethanol (EtOH) and polyoxyethyleneglycol 400 (PEG 400) were added up to 30% to the transport medium as solubilizers. DMSO, EtOH and PEG 400 decreased Pam of hydrocortisone and propranolol. For example, DMSO (30%) decreased Pam of hydrocortisone and propanol by 60 and 70%2, respectively. DMSO and PEG 400 also decreased Pam of ketoprofen. In contrast, EtOH produced an opposite effect on permeability, that is, an increased Pam of ketoprofen. Therefore, the high concentration of these co-solvents could lead to the under- or overestimation of drug permeability. 

The pH-partition theory provides a basic framework for the understanding of drug absorption and, sometimes, is an oversimpiification of a more compiex process. For exampie, experimentaiiy observed pH-absorption curves are iess steep (Fig. 9.12) than that expected... 

Fig. 9. 12. Relationship between absorption rates of salicylic acid and ephedrine and bulk phase pH in the rat small intestine in vivo. Dashed lines represent curves predicted by the pH-partition theory in the absence of an unstirred layer. (From Winne D. The influence of unstirred layers on intestinal absorption in intestinal permeation. In Kramer M, Lauterbach F, eds. Workshop Conference Hoechest, vol 4. Amsterdam Excerpta Medica, 1977 58-64, with permission.)...

For toxicants that are weak acids and bases, the pH partition theory can be used to determine the extent of ionization of a toxicant that in turn can help characterize the extent of absorption. The Henderson-Hasselbach equation relates pH to the percent of compound ionized, as follows ... 

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