A drug's solubility and behaviour in water is particularly important since the cells in our bodies normally contain about 65 per cent water. In living matter water acts as an inert solvent, a dispersing medium for colloidal solutions and a nucleophilic reagent in numerous biological reactions. Furthermore, hydrogen bonding and hydrophobic interactions in water influence the conformations of biological macromolecules, which in turn affect their biological behaviour. Water solubility also makes drug toxicity testing, bioavailability evaluation and clinical application easier. As a result, it is necessary to assess the water solubility of drug candidates and, if required, design a reasonable degree of water solubility into their structures in an early point in their development.
Drugs administered orally as a solid or in suspension have to dissolve in the aqueous gastric fluid (dissolution, see section 11.5.1) before they can be absorbed and transported via the systemic circulation to their site of action. The rate and extent of dissolution of a drug is a major factor in controlling the absorption of that drug. This is because the concentration of the drug (see section 7.3.3) in the fluid in the gut lumen is one of the main factors governing the transfer of the drug through the membranes of the gastrointestinal tract (GI tract). The rate of dissolution depends on the surface area of the solid, which is dependent on both the physical nature of the dosage form of the drug and the chemical structure of the drug. However, the extent of dissolution depends only on the drug's solubility, which depends on the chemical structure of the drug. The dosage form is a formulation problem that is normally beyond the remit of medicinal chemist but the design of the structure of lead compounds with regard to solubility is within the realm of the medicinal chemist.
Once the drug has entered the circulatory system, either by absorption or by direct administration, its water solubility will influence its ease of transport to the body compartments available to that drug. Drugs that are sparingly soluble in water may be deposited on route to their site of action, which can clog up blood vessels and damage organs. For example, many sulphonamides, such as sulphamethoxazole, tend to crystallise in the kidney, which may result in serious liver and kidney damage. Water solubility also affects the ease of drug transport through cell membranes found throughout the general circulatory system.
Although a reasonable degree of water solubility is normally regarded as an essential requirement for a potential drug it is possible to utilise poor water solubility in drug action and therapy. For example, pyrantel embonate, which is used to treat pinworm and hookworm infestations of the GI tract, is insoluble in water. This poor water solubility coupled with the polar nature of the salt means that the drug is poorly absorbed from the gut and so the greater part of the dose is retained in the gastrointestinal tract, the drug's site of action. The low water solubility of a drug can also be used to produce drug depots, chewable dosage forms and mask bitter tasting drugs because taste depends on the substance forming an aqueous solution.
The sulphonamide group h2n^/ Vsonh
The reactivity of water will also affect the stability of the drug in transit. Hydrolysis by water is one of the main routes for the metabolism of drugs containing ester, amide and other hydrolysable groups. For example, one of the metabolic pathways of the local anaesthetic lignocaine is hydrolysis to the amine.
CH3 2 5
The production of compounds with the required degree of water solubility early in the development of a new drug can considerably reduce the overall cost of development since it does not cause any delays in the later stages of development. For example, if it was found to be necessary to produce a water-soluble analogue of a lead compound at a later stage in the development the new analogue would have to be put through the same comprehensive testing procedure as the lead compound. This would necessitate the repeating of expensive toxicity and bioavailability trials, which could result in an expensive delay in the trials programme and possibly production. The importance of water solubility in drug action means that one of the medicinal chemist's development targets for a new drug is s to develop analogues that have the required degree of water solubility.
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