J c c2 c2Pc

The rate of movement across the unstirred layer, as can be seen from the equations, is proportional to D/6; the rate of absorption is proportional to Pc. Compounds with a large permeability coefficient may be able to penetrate across cell membranes much faster than they can be transported through the unstirred layer. Under these circumstances diffusion through the water layer becomes the rate-limiting step in the absorption process. Neglect of the unstirred layer causes errors in the interpretation of experimental flux data.

Effect of the drug

Drugs, as we have seen, must be in their molecular form before diffusional absorption processes take place. We would expect bases to be more soluble than acids in the stomach, but it is impossible to generalise in this way. Although the basic form of a drug as its hydrochloride salt should be soluble to some extent in this medium, this is not always so. Indeed the free bases of, for example, chlor-tetracycline, dimethylchlortetracycline and methacycline are more soluble than their corresponding hydrochlorides in the pH range of the stomach (see Chapter 5). It has been shown that mean plasma levels following administration of the free base and the hydrochloride of these tetracyclines reflect the differences in solubility, the bases giving higher levels. The reason is most likely that discussed in section 5.7.2, namely the influence of high ionic strength on the solubility of the drug substance (the common ion effect). As absorption of the tetracyclines takes place mainly from the duodenum, it is vital that they reach the intestine in a dissolved or readily soluble form, as their solubility is low at the pH conditions prevailing in the duodenum (pH 4-5).

The presence of buffer components in the formulation also creates a pH microenvironment around dissolving particles which may aid drug dissolution. If dissolution is the rate-limiting step in the absorption process, this will be significant in determining absorption. Bulk pH will then give little help in calculating the solution rate on the basis of a knowledge of saturation solubilities in bulk conditions.

Other complicating factors

The very high area of the surface of the small intestine also upsets the calculation of absorption based on considerations of theoretical absorption across identical areas of absorbing surface. The sheer complexity of the situation precludes mathematical precision, yet the pH-partition hypothesis is useful especially in predicting what follows from a change in bulk pH - for example, on ingestion of antacids or drugs such as cimetidine which reduce gastric acid secretion. The extent of the change in pH after administration of cimetidine can be seen from the diagram in Fig. 9.7,which shows a rise in resting pH from below 2 to near neutrality and which in turn depends on the formulation used. The fact that aspirin, an acid with a pKa of 3.5, is absorbed from the small intestine is due partly to the massive surface area available for absorption (which allows significant absorption to occur even though the percentage of absorbable species is very low) and partly to the dynamics of the process referred to earlier.

Figure 9.7 Intragastric pH after administration of (O) effervescent cimetidine and (•) standard cimetidine, plotted as median values from 13 patients with gastro-oesophageal flux given 800 mg orally of the preparations.

Reproduced from M. Ström, S. Madsen and B. Norlander, Lancet, 337, 433 (1991).

Figure 9.7 Intragastric pH after administration of (O) effervescent cimetidine and (•) standard cimetidine, plotted as median values from 13 patients with gastro-oesophageal flux given 800 mg orally of the preparations.

Reproduced from M. Ström, S. Madsen and B. Norlander, Lancet, 337, 433 (1991).

A warning, however: drugs that are unstable in the gastrointestinal tract (for example, erythromycin), drugs that are metabolised on their passage through the gut wall, drugs that are hydrolysed in the stomach to active forms (prodrugs), and drugs that bind to mucin or form complexes with bile salts may not always be absorbed in the manner expected.

Ion pairing

The interaction of drugs in the charged form with other ions to form absorbable species with a high lipid solubility is a possible explanation for the ability of molecules such as quaternary ammonium compounds, ionised under all pH conditions, to be usefully absorbed. The origin of the ions which pair with drug ions is not clear, but there is evidence that ion-pair formation will aid absorption.

One could assume that small organic ions are absorbed through water-filled pores or channels in the membrane, but the effective diameter of such pores means that large drug ions would be excluded from this route. Although membranes are impermeable to large organic ions, nevertheless ion-pairing between a drug ion and an organic ion of opposite charge forming an absorbable neutral species is possible.

Two ionic species A+ and B0 may exist in solution in several states:

A: B undissociated species

'loose' ion pair

The formation of tight or loose ion pairs will depend on solvent-ion interactions: hydro-phobic ions might be encouraged to form ion pairs by the mechanism of water-structure enforced ion pairing in which the water attempts to minimise the disturbance on its structuring, and achieves this end by reducing the polarity of the species in solution by ion-pair formation. Ion pairing in highly structured solvents, then, is due not to an electrostatic interaction but to a solvent-mediated effect. The significance of the phenomenon is that ion pairs have the property of being almost neutral species, so that the ion pair can partition into an oily phase when its parent ionic species cannot, a property that is important in drug absorption and drug extraction procedures, and that is put to use in chromatography.

The two reactions below are examples (i) of a quaternary amine pairing with a weak acid, and (ii) of an alkyl sulfate with a weak base, both under pH conditions in which the solute is charged:


RNH3 O3 SO(CH2) n CH2 hydrophilic ion-pair agent solute hydrophobic ion pair

In extraction procedures using methylene chloride as organic phase, bromothymol blue has been used as an ion-pairing counterion for amfetamine, and picrate ions for atropine. Tetrabutylammonium ion has been used for the extraction of penicillins into chloroform.

Figure 9.8 shows clearly the effect of chloride ion and other anions such as methane sulfonate on the apparent partition coefficient of chlorpromazine. The nature of the anion significantly affects the partitioning of the drug. Ion pairing in the gastrointestinal tract obviously could influence absorption.

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