Bioassayand Standardisation

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Biological assay (bioassay) is the process by which the activity of a substance (identified or unidentified) is measured on living material: e.g. contraction of bronchial, uterine or vascular muscle. It is used only when chemical or physical methods are not practicable as in the case of a mixture of active substances, or of an incompletely purified preparation, or where no chemical method has been developed. The activity of a preparation is expressed relative to that of a standard preparation of the same substance. Biological standardisation is a specialised form of bioassay. It involves matching of material of unknown potency with an International or National Standard with the objective of providing a preparation for use in therapeutics and research. The results are expressed as units of a substance rather than its weight, e.g. insulin, vaccines.

Pharmacokinetics

To initiate a desired drug action is a qualitative choice but. when the qualitative choice is made, considerations of quantity immediately arise; it is possible to have too much or too little of a good thing. To obtain the right effect at the right intensity, at the right time, for the right duration, with minimum risk of unpleasantness or harm, is what pharmacokinetics is about.

Dosage regimens of long-established drugs were devised by trial and error. Doctors learned by experience the dose, the frequency of dosing and the route of administration that was most likely to benefit and least likely to harm. Apart from being laborious and putting patients at risk, this empirical ('suck it and see') approach left some questions unanswered. It did not explain, for example, why digoxin is effective in a once-daily dose, whereas paracetamol may need to be given six times daily; why the same dose of morphine is more effective if it is given intramuscularly than if is taken by mouth; why insulin is useless unless it is injected. The answers to these questions lie in understanding how drugs cross membranes to enter the body, how they are distributed round it in the blood and other body fluids, how they are bound to plasma proteins and tissues (which act as stores) and how they are eliminated from the body. These processes can now be quantified and allow efficient development of dosing regimens.

Pharmacokinetics5 is concerned with the rate at which drug molecules cross cell membranes to enter the body, to distribute within it and to leave the body, as well as with the structural changes {metabolism) to which they are subject within it.

The subject will be discussed under the following headings:

• Drug passage across cell membranes

• Order of reaction or process (first- and zero-order)

• Time course of drug concentration and effect Plasma half-life and steady-state concentration Therapeutic monitoring

• The individual processes Absorption Distribution

Metabolism (biotransformation) Elimination.

Certain concepts are fundamental to understanding how drug molecules make their way around the body to achieve their effect. The first concerns the modes by which drugs cross cell membranes and cells.

Our bodies are labyrinths of fluid-filled spaces. Some, such as the lumina of the kidney tubules or

5 Greek: pharmacon drug, kinein to move.

intestine, are connected to the outside world; the blood, lymph and cerebrospinal fluid are enclosed. Sheets of cells line these spaces and the extent to which a drug can cross epithelia or endothelia is fundamental to its clinical use. It is the major factor that determines whether a drug can be taken orally for systemic effect and whether within the glomerular filtrate it will be reabsorbed or excreted in the urine.

Cell membranes are essentially bilayers of lipid molecules with 'islands' of protein and they preserve and regulate the internal environment. Lipid-soluble substances diffuse readily into cells and therefore throughout body tissues. So-called tight junctions, some of which are traversed by water-filled channels through which water-soluble substances of small molecular size may filter, link adjacent epithelial or endothelial cells. The jejunum and proximal renal tubule contain many such channels and are called leaky epithelia, whereas the tight junctions in the stomach and urinary bladder do not have these channels and water cannot pass; they are termed tight epithelia. Special protein molecules within the lipid bilayer allow specific substances to enter or leave the cell preferentially (carrier proteins). The natural processes of passive diffusion, filtration and carrier-mediated transport determine the passage of drugs across membranes and cells.

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