Oral drug absorption is a critical process that determines the efficacy and safety of a medication. The bioavailability of a drug depends on various factors, including physical properties, dosage forms, physiological factors, pharmacogenetic factors, and disease states. This article discusses these factors in detail to understand how they affect the absorption and bioavailability of orally administered drugs.
I. Physical Properties:
The physical properties of a drug play a crucial role in its absorption and bioavailability. These include:
1. Physical state:
Liquids are absorbed better than solids, and crystalloids are absorbed better than colloids. For instance, the syrup is absorbed more rapidly than a tablet because the syrup is already in a dissolved state. Therefore, it is easier for the body to absorb the medication.
2. Lipid or water solubility:
Drugs in aqueous solutions mix more readily than those in oily solutions with the aqueous phase at the absorption site and hence are absorbed faster. However, at the cell surface, the lipid-soluble drugs penetrate into the cell more rapidly than the water-soluble drugs. Bile salts emulsify the fat-soluble vitamins A and D in the small intestine and assist their absorption.
II. Dosage Forms:
The dosage form of medication also affects its absorption and bioavailability. These factors include:
1. Particle size:
The particle size of sparingly soluble drugs can affect their absorption. A tablet that contains large aggregates of the drug may not disintegrate even on prolonged contact with gastric and intestinal juices and hence, may be poorly absorbed. Small particle size is important for the absorption of corticosteroids, antibiotics like chloramphenicol and griseofulvin, certain oral anticoagulants, and spironolactone. By reducing the particle size, the dosage of the active drug can be reduced without lowering its efficacy. On the other hand, for an antihelminthic such as bephenium hydroxynaphthoate, the particle size should be large enough to reduce its absorption. Particle size is of no consequence in the case of freely water-soluble drugs.
2. Disintegration time and dissolution rate:
The effect of the physical factors is commonly evaluated by determining:
(i) The disintegration time, which measures the rate of break up of the tablet or the capsule into the drug granules; and
(ii) The dissolution rate, which is the rate at which the drug goes into solution.
The disintegration time of a tablet is a poor measure of the bioavailability of the contained drug. This is because, in addition to disintegration time and particle size, other factors such as crystalline form (polymorphism), saturation solubility, and solvation can modify the bioavailability of a drug. The dissolution rate is perhaps a better parameter.
The method of the formulation can markedly influence drug absorption and thus determine its bioavailability. Usually, substances like lactose, sucrose, starch, calcium phosphate, or lactate are used as inert diluents in formulating powders or tablets. Such fillers may not be entirely inert but may affect the absorption as well as stability of the medicament. Thus, calcium and magnesium ions reduce the absorption of tetracyclines, while calcium phosphate used as a diluent for calciferol has caused calcium toxicity when given in large doses. Replacement of calcium phosphate by lactose made a marked difference in the efficacy of a reformulated phenytoin preparation. A faulty formulation can render a useful drug therapeutically useless.
III. Physiological Factors:
The physiological factors that affect the absorption and bioavailability of orally administered drugs include:
The mucosal lining of the GI tract is impermeable to ionized forms of weak organic acids and weak organic bases. At the body pH, most drugs exist in two forms: (1) an un-ionized component, predominantly lipid-soluble; and (2) an ionized, water-soluble component. The unionized fraction can cross the cell membrane rapidly. The amount of the drug that crosses the gut wall is determined by the gradient of its concentration between the lumen of the gut and the portal venous blood. If the plasma concentration of a drug present in a free, un-ionized form is rapidly reduced by binding with plasma proteins, its absorption from the gut lumen is enhanced.
2. pH of the GI fluid and the blood:
Weakly acidic drugs are rapidly absorbed from the stomach as they exist in the acidic medium of the stomach in an unionized form. They act quickly on oral administration, e.g., salicylates and barbiturates. However, most of the weakly acidic drugs are also absorbed from the duodenum because of their solubility in the alkaline medium and the large absorbing surface area. Weakly basic drugs are not absorbed until they reach the alkaline environment of the small intestine. The alkaline environment, in which the drugs exist in an unionized form, facilitates their absorption. Their actions are delayed when administered orally, e.g., pethidine and ephedrine.
At the pH values found in the intestine, the strongly acidic or basic drugs are highly ionized and hence, they are poorly absorbed. Aminoglycosides are strong bases, and hence, their absorption from the GI tract is poor.
3. GI transit time:
The presence of food and the volume, viscosity, and tonicity of the gastric contents can influence drug absorption by altering the gastric emptying time. Rapid absorption occurs if the drug is given on an empty stomach.
Increased peristaltic activity, as in diarrhea, reduces drug absorption. Anticholinergic drugs, which prolong gastric emptying time, also impair the absorption of drugs.
4. Enterohepatic cycling:
5. Area of the absorbing surface and local circulation:
Drugs are absorbed better from the small intestine than from the stomach because of the larger surface area of the former. Reduction in the absorbing surface following major GI resection reduces drug absorption. Increased vascularity can increase absorption.
6. First pass elimination:
The bioavailability of certain drugs is reduced by rapid metabolic degradation during the first passage through the gut wall (isoprenaline) or the liver (propranolol). The other examples are opioids, beta-adrenergic blockers, progesterone, isosorbide dinitrate, etc.
7. Presence of other agents:
Vitamin C enhances the absorption of oral iron, while phytates retard it. The absorption of fat-soluble vitamins is reduced in the presence of liquid paraffin, whereas cholesterol absorption is reduced by sitosterol. Calcium, present in milk and in antacids, forms insoluble complexes with the tetracyclines and reduces absorption.
IV. Pharmacogenetic factors:
Pharmacogenetics is the study of how genetic variation affects the response to drugs. Pharmacogenetic factors can significantly affect drug absorption and bioavailability. For example, genetic variations in the drug-metabolizing enzymes or drug transporters can lead to differences in the metabolism and disposition of drugs. This can result in differences in drug absorption and bioavailability between individuals with different genotypes.
V. Disease States:
Certain disease states can also affect drug absorption and bioavailability. Structural changes in the GI mucous membrane can result in malabsorption syndrome. Gastrointestinal mucosal edema significantly depresses the absorption of drugs such as hydrochlorothiazide in patients with congestive heart failure. Absorption and first-pass metabolism may be affected in conditions like thyrotoxicosis, achlorhydria, cirrhosis of the liver, and biliary obstruction.
The only valid tests of the bioavailability of a drug preparation are the levels of the drug in biological fluids such as plasma, urine, and saliva and an objectively measurable parameter of its therapeutic efficacy, e.g., heart rate and BP. Therapeutically, bioavailability is more important in the case of drugs with a narrow therapeutic index, e.g., digoxin and aminophylline.
In conclusion, the absorption and bioavailability of orally administered drugs are affected by various factors, including physical properties, dosage forms, physiological factors, pharmacogenetic factors, and disease states. A thorough understanding of these factors is essential for the development of effective drug formulations and dosing regimens.
Disclaimer: This article is for informational purposes only and should not be taken as medical advice. Always consult with a healthcare professional before making any decisions related to medication or treatment.
1. How can physical properties affect drug absorption and bioavailability?
Physical properties like physical state and lipid or water solubility can affect drug absorption and bioavailability.
2. What are the factors that affect the dissolution rate of a drug?
The dissolution rate of a drug is affected by factors like particle size, disintegration time, and the method of formulation.
3. How do physiological factors like ionization and pH affect drug absorption?
Ionization and pH affect drug absorption by affecting the solubility and permeability of the drug across the GI tract mucosa.
4. How do pharmacogenetic factors affect drug absorption and bioavailability?
Pharmacogenetic factors can lead to differences in drug metabolism and disposition, which can affect drug absorption and bioavailability.
5. Why is bioavailability important in the case of drugs with a narrow therapeutic index?
Bioavailability is important in the case of drugs with a narrow therapeutic index because even small changes in drug absorption can lead to significant changes in therapeutic efficacy and toxicity.