solubility of the agent in biological lipid phases, there will be some relationship between pharmacodynamic activity and drug solubility. On the other, we should expect that drug or drug salt solubility might influence the absorption phase; drugs of very low aqueous solubility will dissolve slowly in the gastro-intestinal tract, and in many cases the rate of dissolution is the rate-controlling step in absorption.

With drugs of low aqueous solubility such as digoxin, chlorpropamide, indometacin, griseofulvin, and many steroids, the physical properties of the drug can influence biological properties. At early stages in a drug's development, pharmacological and toxicological tests are frequently carried out on extemporaneously prepared suspensions whose physical characteristics are not always well defined. This is not good practice as the toxicity of some drugs given by gavage to rats is dependent on the drug species used13 (Table 5.15). This has been shown to be true with polymorphic forms of the same drug, but in the cases discussed in Table 5.15 different salts of the drugs were used.

There are other examples in which aqueous solubility acts as a rough and ready guide to

Table 5.15 The effect of solubility in water on the toxicity of drugs given by gavage to albino ratsa




Benzylpenicillin Ammonium <20 mg cm 3 8.4 ± 0.13 Benzylpenicillin Potassium >20 mg cm03 6.7 ± 0.1

Iron Iron

Spiramycin Spiramycin

Free metal Ferrous sulfate Free base Adipate

Insoluble Soluble

a Modified from reference 13.

absorption characteristics. Of the cardiotonic glycosides digitoxin, digoxin and ouabain, the least water soluble, being the most lipid soluble, is best absorbed. But because of the lipophilicity of digitoxin and digoxin, the rate-limiting step is the rate of solution, which is influenced directly by the solubility of the compounds.

High molecular weight quaternary salts such as bephenium hydroxynaphthoate (XXI) and pyrvinium embonate (XXII), being quaternary, have low lipid solubility but also have

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