Systemic Availability And Bioavailability

When a drug is injected intravenously it enters the systemic circulation and thence gains access to the tissues and to receptors, i.e. 100% is available to exert its therapeutic effect. If the same quantity of the drug is swallowed, it does not follow that the entire amount will reach first the portal blood and then the systemic blood, i.e. its availability for therapeutic effect via the systemic circulation may be less than 100%. The anticipated response to a drug may not be achieved unless availability to the systemic circulation is taken into account. In a strict sense, considerations of reduced availability apply whenever any drug intended for systemic effect is given by any route other than the intravenous, but in practice the issue concerns enteral administration. The extent of systemic availability is ordinarily calculated by relating the area under the plasma concentration-time curve (AUC) after a single oral dose to that obtained after i.v. administration of the same amount (by which route a drug is 100% systemically available). Different pharmaceutical formulations of the same drug can thus be compared. Factors influencing systemic availability may be thought of in three main ways:

Pharmaceutical factors.8 The amount of drug that is released from a dose form (and so becomes available for absorption) is referred to as its bioavailability. This is highly dependent on its pharmaceutical formulation. With tablets, for example, particle size (surface area exposed to solution), diluting substances, tablet size and pressure used in the tabletting machine can affect disintegration and dissolution and so the bioavailability of the drug.

Manufacturers are expected to produce a formulation with an unvarying bioavailability so that the same amount of drug is released with the same speed from whatever manufactured batch or brand the patient may be taking. Substantial differences in bioavailability of digoxin tablets from one manufacturer occurred when only the technique and machinery for making the tablets were changed; also tablets containing the same amount

8 Some definitions of enteral dose-forms: Tablet: a solid dose form in which the drug is compressed or moulded with pharmacologically inert substances (excipients); variants include sustained-release and coated tablets. Capsule: the drug is provided in a gelatin shell or container. Mixture: a liquid formulation of a drug for oral administration. Suppository: a solid dose-form shaped for insertion into rectum (or vagina, when it may be called a pessary)', it may be designed to dissolve or it may melt at body temperature (in which case there is a storage problem in countries where the environmental temperature may exceed 37°C); the vehicle in which the drug is carried may be fat, glycerol with gelatin, or macrogols (polycondensation products of ethylene oxide) with gelatin. Syrup: the drug is provided in a concentrated sugar (fructose or other) solution. Linctus: a viscous liquid formulation, traditional for cough.

of digoxin but made by different companies, were shown to produce different plasma concentrations and therefore different effects, i.e. there was neither bioequivalence nor therapeutic equivalence. Physicians tend to ignore pharmaceutical formulation as a factor in variable or unexpected responses because they do not understand it and feel entitled to rely on reputable manufacturers and official regulatory authorities to ensure provision of reliable formulations. Good pharmaceutical companies reasonably point out that, having a reputation to lose, they take much trouble to make their preparations consistently reliable. This is a matter of great importance when dosage must be precise (anticoagulants, antidiabetics, adrenal steroids). The following account by Lauder Brunton in 1897 indicates that the phenomenon of variable bioavailability is not recent.

A very unfortunate case occurred some time ago in a doctor who had prescribed aconitine to a patient and gradually increased the dose. He thought he was quite certain that he knew what he was doing. The druggist's supply of aconitine ran out, and he procured some new aconitine from a different maker. This turned out to be many times stronger than the other, and the patient unfortunately became very ill. The doctor said, 'It cannot be the medicine', and to show that this was true, he drank off a dose himself with the result that he died. So you must remember the difference in the different preparations of aconitine,9

i.e. they had different bioavailability and so lacked therapeutic equivalence.

Biological factors. Those related to the gut include destruction of drug by gastric acid, e.g. benzyl-penicillin, and impaired absorption due to intestinal hurry which is important for all drugs that are slowly absorbed. Drugs may also bind to food constituents, e.g. tetracyclines to calcium (in milk), and to iron, or to other drugs (e.g. acidic drugs to cholestyramine) and the resulting complex is not absorbed.

Presystemic (first-pass) elimination. Despite the

9 The doctor would have died of cardiac arrhythmia and/or cerebral depression. Aconitine is a plant alkaloid and has no place in medicine.

fact that they readily enter gut mucosal cells, some drugs appear in low concentration in the systemic circulation. The reason lies in the considerable extent to which such drugs are metabolised in a single passage through the gut wall and (principally) the liver. This is a significant feature of the oral route, and as little as 10-20% of the parent drug may reach the systemic circulation unchanged. By contrast, if the drug is given intravenously, 100% becomes systemically available and the patient is exposed to higher concentrations with greater, but more predictable, effect. If a drug produces active metabolites, differences in dose may not be as great as those anticipated on the basis of differences in plasma concentration of the parent drug after intravenous and oral administration. Once a drug is in the systemic circulation, irrespective of which route is used, about 20% is subject to the hepatic metabolic processes in each circulation because that is the proportion of cardiac output that passes to the liver.

As the degree of presystemic elimination differs much between drugs and between individuals, the phenomenon of first-pass elimination adds to variation in systemic plasma concentrations, and thus particularly in initial response to the drugs that are subject to this process. When a drug is taken in overdose, presystemic elimination may be reduced, and bioavailability increased; this may explain rapid onset of toxicity with antipsychotic drugs, many of which undergo first-pass elimination.

Drugs for which presystemic elimination is significant include:

Analgesics

Adrenoceptor blockers

Others

dextropropoxyphene

labetalol

clomethiazole

morphine

propranolol

chlorpromazine

pentazocine

metoprolol

isosorbidc

pethidine

oxprenolol

dinitrate

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