Introduction to Biopharmaceutics and Absorption
1.1.1. Introduction
Drugs are used in the diagnosis, cure, mitigation, treatment, or prevention of diseases. They are given in various dosage forms, such as solids (tablets, capsules, etc.), semisolids (ointments, creams, etc.), liquids, suspensions, emulsions, etc., for systemic or local therapeutic activity. Drug products are drug delivery systems that deliver and release drug at the action site so that they produce the desired therapeutic effect. These products are also designed to ful fil the patient’s requirements including palatability, convenience, and safety. Release of drug substance from the drug product either for local drug action or for plasma drug absorption for systemic therapeutic action defines the drug product performance .
Advancements in pharmaceutical technology and manufacturing have led to the development of safer, more effective, and more patient convenient quality drug products. Biopharmaceutics is defined as, ―study of the interrelationship of physicochemical properties of the drug, dosage form in which the drug is given and the administration route on the rate and extent of systemic drug absorption.‖ Biopharmaceutics is also defined as ―study of the factors influencing the rate and amount of drug that reaches the systemic circulation and the use of this information to optimise the therapeutic efficacy of drug products.‖
1.1.2. Applications of Biopharmaceutics
The field of biopharmaceutics has the following applications:
1) When a newly developed dosage form by a company is given to human beings, sometimes the drug is released slowly and sometimes the entire drug is released at a time; both these situations are not useful. Thus, the principles of biopharmaceutics are utilised to obtain the required action from the formulation.
2) When a company wishes to change the ingredients of tablet dosage forms, the altered ingredients will be approved by the FDA only if the bioavailability is equal to the initial formulation. Thus, the principles of biopharmaceutics are utilised to study the bioavailability of the new ingredients.
3) When a company wishes to change a drug’s administration route from oral to transdermal, bioavailability of the drug is compared from both the routes and will be released only if the bioavailability is similar. Thus, the principles of biopharmaceutics are utilised to study the bioavailability of the drug.
ABSORPTION
1.2.1. Introduction
The desired therapeutic objective can be achieved if the drug product delivers the active drug at an optimal rate and extent. If a proper biopharmaceutical design is maintained, the rate and extent of drug absorption (or bioavailability) or the systemic delivery of drug into the body can be altered from rapid and complete absorption to slow and sustained absorption; however, this depends on the desired therapeutic action. The events that occur after a solid dosage form (a tablet or a capsule) is administered until its absorption in the systemic circulation are shown in the figure 1.1.
These events comprise of the following four steps:
1) Disintegration of the drug product,
2) De-aggregation and release of the drug,
3) Dissolution of the drug in aqueous fluids at the absorption site, and
4) Movement of the dissolved drug throug h the gastrointestinal membrane into the systemic circulation and away from the absorption site.
A drug molecule gets absorbed from the GIT and enters the systemic circulation only if it effectively penetrates all the intestinal regions. Once the drug ent ers the solution, its absorption is governed by the following three important factors:
1) The physicochemical properties of the drug molecule,
2) The properties and components of the GI fluids, and
3) The nature of the absorbing membrane.
1.2.2. Mechanisms of Drug Absorption Through GIT
The drug after entering the GI fluids exists in the form of a solution and can get absorbed. The drug’s physicochemical properties (its inherent absorbability) and the environmental properties around i t (such as pH, presence of interfering materials, and local properties of the absorbing membrane) decide whether or not the drug is in absorbable form. If there are no interfering materials (that affect
drug absorption), the drug molecule diffuses from the GI fluids to enter the absorbing membrane surface. A drug molecule gets absorbed from the GIT and enters the systemic circulation only if it effectively penetrates all the intestinal regions. The pathways of drug transport show that drug absorption from the GI lumen into the systemic circulation involves the passage of drug molecules across several cellular membranes and fluid regions in the mucosa, i.e., the gastrointestinal-blood barrier. The GIT epithelium lining is the major cellular barrier to the a bsorption of drugs from the GIT. The drug molecules in GI fluids should cross the unstirred aqueous layer, mucus layer, and glycocalyx to reach the apical cell membrane. The following mechanisms are involved in the transport of drug molecules across the cell membrane: 1) Passive diffusion,
2) Carrier-mediated transport:
i) Facilitated diffusion, and ii) Active transport,
3) Pore transport,
4) Ionic or electrochemical diffusion,
5) Ion-pair transport, and
6) Endocytosis.
1.2.2.1. Passive Diffusion
Passive diffusion (or non-ionic diffusion) is the major process for absorption of more than 90% of drugs. It is defined as the difference in the drug concentration on either side of the membrane. Concentration or electrochemical gradient is the driving force for this process.
The kinetic energy of drug molecules is responsible for the movement of drug. Since no energy source is required, the process is called passive diffusion, during which the drug in the aqueous solution at the absorption site, partitions and dissolves in the lipid material of the membrane and leaves it by dissolving in an aqueous medium at the inside of the membrane.
1.2.2.2. Carrier-Mediated Transport
Some polar drugs pass through the membrane more rapidly than can be predicted from their concentration gradient and p artition coefficient values. This is due to the presence of a specialised transport mechanism, without which monosaccharides, amino acids, and vitamins (essential water -soluble nutrients) will undergo poor absorption. The mechanism involves a membrane component, called the carrier that reversibly or non -covalently binds to the solute molecules to be transported. This carrier -solute complex crosses the membrane to reach the other side, where it dissociates and releases the solute molecule; after which, th e carrier returns to its original site and accepts a fresh solute molecule, thereby completing the cycle.
Carrier-mediated transport system is of two types:
1) Facilitated diffusion, and
2) Active transport.
1.2.2.3. Facilitated Diffusion
Facilitated diffusion is a carrier -mediated transport system that works at a much faster rate than the passive diffusion. Concentration gradient is the driving force for this process that operates down the hill and thus is a passive process.
Since the process involves down-hill transport, there is no expenditure of energy, and the system is not inhibited by metabolic poisons. Some applications of facilitated diffusion system in drug absorption are: 1) Its major application involves entry of glucose into RBCs.
2) Another application involves intestinal absorption of vitamins B1 and B2.
3) The most significant application involves gastrointestinal absorption of vitamin B 12 (figure 1. 4), which forms a complex with glycopro tein [an Intrinsic Factor (IF) produced by gastric parietal cells]; and then this complex is transported across the intestinal membrane through a carrier system.
1.2.2.4. Active Transport
Active transport i nvolves movement of a substance from a region of low concentration to high concentration, i.e., against its concentration gradient. In all the cells, this is concerned with accumulating high concentrations of ions, glucose, and amino acids that the cell requires (figure 1.5).
Active transport utilises energy, unlike passive transport that does not use any type of energy. If it uses chemical energy from ATP, it is termed as primary active transport. If it uses an electrochemical gradient, it is termed as secondary active transport.
The significance of active transport pro cess in the absorption of nutrients and drugs is more than the facilitated diffusion, and both the processes differ in the following aspects:
1) In active transport, drug is transported from a region of lower concentration to a region of higher concentration, i.e., against the concentration gradient or uphill transport.
2) Active transport is an uphill process, thus energy is required in the work done by the carrier.
3) Active transport process requires energy, thus it can be inhibited by metabolic poisons (like flu orides, cyanides, di -nitrophenol, lack of oxygen, etc.) that interfere with energy production.
Sodium, potassium, calcium, iron, glucose, certain amino acids, and vitamins like niacin, pyridoxine and ascorbic acid are the endogenous substances that are actively transported. Drugs that are structurally similar to such agents (mainly the agents used in cancer chemotherapy) are actively absorbed. For example, absorption of 5- fluorouracil and 5-bromouracil through pyrimidine transport system;absorption of methyldopa and levodopa through L-amino acid transport system; and absorption of enalapril (ACE inhibitor) through small peptide carrier system. An example of competitive inhibition of drug absorption through active transport is the impaire d absorption of levodopa when taken with protein -rich meals. Active transport is also important in renal and biliary excretion of many drugs and their metabolites and secretion of certain acids out of the CNS.
1.2.2.5. Pore Transport
Pore transport (or connective transport, bulk flow or filtration) involves the absorption of low molecular weight, low molecular size, and water -soluble drugs (e.g., urea, water, and sugar) through narrow, aqueous filled channels o r pores in the membrane structure. This mechanism facilitates the transport of molecules into the cell through protein channels present in the cell membrane. Chain-like or linear compounds of 400 Daltons molecular weight can be observed by filtration. Hydrostatic pressure or the osmotic differences across the membrane is the driving force for this process. Due to this, bulk flow of water along with small solid molecules occurs through such aqueous channels. Water flux promoting such a transport is called as solvent drag. Drug permeation through water-filled channels is significant in renal excretion, removal of drug from the cerebrospinal fluid, and entry of drugs into the liver.
1.2.2.6. Ionic or ElectrochemicalDiffusion
Ionic or electrochemical diffusion involves the diffusion of ionic molecules across the membrane as a function of potential difference or electrical gradient; while non-ionic diffusion involves the diffusion of uncharged mol ecules. No matter ionic drug molecules diffuse through the membrane at a slower rate than the lipid-soluble, uncharged molecules, still they undergo significant absorption. The outer surface of membrane is positively charged, while its intracellular
surface carries negative charge. Cationic drugs, due to the repulsion between similarly charged molecules, show electrostatic repulsion on the outer surface of the membrane. Thus, the molecules with a high kinetic energy can only cross the membrane barrier. On t he other hand, cationic drugs inside the membrane undergo significant interaction with the negatively charged intracellular membrane, and create the electrical gradient, causing electrical diffusion. Electrochemical diffusion is the function of electrical field as well as the concentration difference across the membrane, and this process lasts till equilibrium is achieved.
1.2.2.7. Ion-Pair Transport
Drugs with a Zwitter ion undergo ionisation over the enti re pH range of the GIT, e.g., ampicillin, amoxicillin, and tetracycline. Smaller ionic drugs travel through the water -filled pores; but, the Zwitter ionic drugs are large enough to pass through the water -filled pores and are also highly lipid insoluble to partition through lipoidal membrane. Thus, these drugs utilise their charge to pair with the endogenous ions of the GIT and cross the membrane. The resulting paired molecule partitions into the lipoidal membrane (figure 1. 6). These drugs are ionic, but sho w passive absorption and maximum partition coefficient when the net charge on the molecule is minimum
1.2.2.8. Endocytosis
Endocytosis is a minor transport mechanism in which the extracellular materials are engulfed within a segment of the cell membrane to form a saccule or a vesicle, which is then pinched -off intracellularly (figure 1.7). Thus, this process is also called as corpuscular or vesicular transport.
The process of endocytosis helps in the cellular uptake of macromolecular nutrients (like fats and starch), oil -soluble vitamins (like A, D, E, and K), and drugs (like insulin). This process is also significant because since the drug is absorbed into the lymphatic circulation, it bypasses first-pass hepatic metabolism.
Types of Endocytosis
The process of endocytosis is of the following two types:
1) Phagocytosis (Cell Eating): This process involves adsorptive uptake of solid particulates.
2) Pinocytosis (Cell Drinking ): This process i nvolves uptake of fluid solute; for example , orally administered Sabin polio vaccine and large protein molecules are absorbed by pinocytosis. At times, transcytosis occurs in which an endocytic vesicle is transferred from one extracellular compartment to another.
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