What are the factors affecting bioavailability of orally administered drug?

Answer 1

Many factors can contribute to affect the bioavailability of the orally administered drugs. Briefly, these includes gastric emptying rate, intestinal transit time, hepatic first pass metabolism, and gastrointestinal and hepatic blood flow etc. apart from these factors, disease conditions, diet and dosage form also contribute in alteration of the bioavailability of the drugs.

Answer 2

The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one (i.e. F<1). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation,

Such factors may include, but are not limited to:

Physical properties of the drug (hydrophobicity, pKa, solubility)

The drug formulation (immediate release, excipients used, manufacturing methods, modified release - delayed release, extended release, sustained release, etc.)

If the drug is administered in a fed or fasted state

Gastric emptying rate

Circadian differences

Enzyme induction/inhibition by other drugs/foods:

Interactions with other drugs (e.g. antacids, alcohol, nicotine)

Interactions with other foods (e.g. grapefruit juice, pomello, cranberry juice)

Transporters: Substrate of an efflux transporter? (e.g. P-glycoprotein)

Health of the GI tract

Enzyme induction/inhibition by other drugs/foods:

Enzyme induction (increase rate of metabolism). e.g. Phenytoin (antiepileptic) induces CYP1A2, CYP2C9, CYP2C19 and CYP3A4

Enzyme inhibition (decrease rate of metabolism). e.g. grapefruit juice inhibits CYP3A --> higher nifedipine concentrations

Individual Variation in Metabolic Differences

Age: In general, drugs metabolized more slowly in fetal, neonatal, and geriatric populations

Phenotypic differences, enterohepatic circulation, diet, gender.

Disease state

e.g. hepatic insufficiency, poor renal function

Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation). Whether a drug is taken with or without food will affect absorption, other drugs taken concurrently may alter absorption and first-pass metabolism, intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora. Disease states affecting liver metabolism or gastrointestinal function will also have an effect.

Relative bioavailability is extremely sensitive to drug formulation. Relative bioavailability is one of the measures used to assess bioequivalence between two drug products, as it is the Test/Reference ratio of AUC. The maximum concentration of drug in plasma or serum (Cmax) is also usually used to assess bioequivalence. When Tmax is given, it refers to the time it takes for a drug to reach Cmax.

Answer 3

15. Factors affecting biological activity

Various aspects of bioactivity apply to any chemical whether of natural or syn-thetic origin. These aspects will be dealt with briefly and are:

15.1. Physicochemical properties

These relate to the transport of the bioactive compound to its site of action, usu-ally a receptor or other biomacromolecule at the cellular or subcellular level. Underexperimental conditions, either in vivo or clinical, or real life conditions, the extent towhich a drug passes through semi-permeable membranes before reaching its site oraction depends on its solubility.Under in vitro conditions, many or these barriers are absent. In vitro bioactivitytherefore represents only a stage in this basic assessment of pharmacological effects.In plant drug research, the solubility of active constituents may be revealed fromextraction procedures. Extraction programmes separate lipophilic constituents fromwater-soluble compounds. Further extraction of an extract may lead to furtherrefinement of physicochemical properties.After the bioactive molecular entity has been identified, detailed data on solubil-ity, partition coefficients and the electrolytic behaviour can be determined. Solubilitycharacters are closely related to drug absorption and the degree of absorption is animportant determinant or drug action. Many bioactive plant constituents are weak

A. Gurib-Fakim / Molecular Aspects of Medicine 27 (2006) 1-93

41

acids and bases, and their degree or ionization when dissolved, is or great importanceto their bioactivity. As a rule, the ionic form is more water-soluble.These factors are important when bioactivity is regarded in the context of drugdistribution between intestine and plasma, between kidney tubules and urine, andbetween plasma and other body compartments. Generally, but simplified, one maysay that only the lipid-soluble and un-dissociated forms of a bioactive molecule willpass through membranes. However, at the site of action, bioactive compounds maygenerate their action by binding to a receptor on the cell membrane.

15.2. Chemical parameters

The structural features of a compound can be related to its pharmacological prop-erties, either qualitatively or quantitatively. The principles, concepts and numericalrules governing qualitative and quantitative relationships between structure andactivity help explain the pharmacological activity of a new compound, which iswhy it is important to evaluate the structure of a newly isolated plant compound.The basic aspects of molecular structures involved in bioactivity include:

•

Resonance and Inductive effect

: This is a phenomenon that a molecule can be rep-resented by two or more structures that differ only in their electron, but notatomic arrangement. The electron density and electron distribution patterns helpexplain the molecule

Õ

s activity and hence its molecular interaction and bioactivity.While resonance is explained as at above, inductive effect is measurable electro-static phenomenon caused by actual electron shiftor displacements along chemicalbonds. Both negative and positive inductive effects can lead to a change inbioactivity.

•

Oxidative and reductive potentials

: This phenomenon represents the tendency of acompound to lose or gain electrons. Electron transfer is vital for living processesand without which living cells would not function. Bioactive compounds derivedfrom plant sources function in enzyme systems in plants in the same way to thosein animals or humans.

•

Types of bonding

: The phenomenon of biological activity is concerned with cova-lent and non-covalent interactions. Covalent bonds are formed enzymatically andare common to all biomolecules. Hydrogen bonds, ionic forces, hydrophobic (orlipophilic bonding), charge-transfer interactions, all representing non-covalentinteractions are also common to functional life processes. Some agents can affectphysiological functions by forming irreversible covalent bonds with target bio-macromolecules and these molecules would be considered to be toxic at cellularlevel and would be difficult to control clinically and medically. In plant drugresearch, agents exerting their activity through much weaker and reversible bond-ing process would be desirable.

•

Spatial arrangement of the molecule

: In terms of activity, it is important to have agood steric and electronic complementarity between ligand and target biomole-cule. Bioactive compounds interact with enzymes by fitting sterically into a bind-ing pocket-the space sterically provided by these targets. Thus the molecular

42

A. Gurib-Fakim / Molecular Aspects of Medicine 27 (2006) 1-93

dimensions, interatomic distances, arrangements of electrons and the stereochem-ical properties of both ligand and target are decisive in determining biologicalactivity