Bioavailability - Pharmaceutical Chemicals: Management

BIOAVAILABILITY

According to a biopharmaceutic expert, the term bioavailability may be defined as the rate and extent to which the ingredient is absorbed from the drug product into the body or to the site of action. It is measured by blood, serum or plasma levels or from urinary excretion data.

1. Importance

There are three major factors that govern the efficacy of a dosage form, namely :

(a) Onset of therapeutic activity.

(b) Intensity of the therapeutic effect.

(c) Duration of the therapeutic effect.

The above three factors are solely responsible for the rate of absorption of the drug, the distribution of the drug throughout the circulatory system and above all the elimination of the active principle from the body.

Official quality control methods adopted, e.g., disintegration time and dissolution rate, do not give ample therapeutic equivalence among drug products belonging to the same class. Moreover, even the products of the same manufacturer may have varying degree of bioavailability in different batches. Therefore, it has become quite necessary to introduce comparative bioavailability studies and skillfully designed fool-proof clinical tests of therapeutic equivalence as an effective true remedial measure of the ultimate performance of drug products.

In 1968, fifty-one patients suffered from an epidemic of anticonvulsant intoxication in Brisbane. A thorough investigation revealed that the intoxication was caused by altering one of the excipients from calcium phosphate to lactose in the drug product Phenytoin Capsule without adequate pre-testing by the manufacturer.

This apparent minor change of excipient was sufficient enough to bring about an appreciable major change in enhancing the bioavailability of the active principles to abnormally high levels in the affected patients.

2. Question of Quality

It has now been established beyond any reasonable doubt that quality of a drug product cannot simply be ensured by inspection or analysis, but a control system has to be built into, from the very beginning of manufac-ture of a drug. Besides effective quality control measures exercised in every aspects of production including environment, screening of raw materials, process controls, intermediate shelf-life of finished products the most important aspect is to assess the bioavailability of the active principle.

Difference in bioavailability, particularly in drugs with low solubilty, as ascertained by blood level attainment studies, appears to be caused by a number of formulation variables, namely : particlesize, crystalline structure, binding or disintegrating agent, excipient etc., on the release pattern of the drug in its dosage from. For example : the rate of dissolution of the drug in tablet or a capsule in the gastrointestinal fluids.

3. Clinical Efficacy of Drugs

Medical scientists mainly rely on the measurement of bioavailability of a drug as a positive indicator of therapeutic equivalence, because clinical efficacy for orally administered drugs depends on the degree of absorption and the presence of the active ingredient in the blood stream.

Technical information based on in vivo standards and specifications are generally incorporated in vari-ous official compendia. Hence, in order to record a legitimate assessment of bioavailability, in vivo test is an absolute necessity and the relative data obtained therefrom should form an integral part of the standard specifi-cations in the offcial standard.

4. Adverse Drug Reaction

Any dosage-form can produce adverse drug reactions. Hence, a regular feed back of relevant informa-tion on such adverse reactions from the medical practitioners to the appropriate regulatory authorities and the concerned manufacturers would not only help to intensify better safety measures but also widen the scope to improve drug-design by meticulous research scientists all over the world.

The following two examples convey the implications of adverse-drug reaction. They are :

Example 1 : Aspirin—Increased gastric damage and subsequent bleeding caused by some aspirin fomulations have been specifically attributed to the slowly dissolving aspirin particles in the stomach. However, both effervescent and highly buffered dosage forms (antacid-aspirin-tablet), which help in maintaining the aspirin in solution, have been found to minimise gastro-intestinal toxicity.

Example 2 : Chloramphenicol and Tetracycline—Sparingly soluble broad-spectrum antibiotics like chloramphenicol and tetracycline found to damage the gastrointestinal epithelium besides changing the normal micro-flora in the GI-tract that are required for normal good health.