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Lakshmana Prabu, T. Suriyaprakash, K. Ruckmani and R. Drug research is a specific process toward the development of new therapeutic agents in this era to meet the current medical needs. Drug discovery and development are the two major stages in the development of new therapeutic drug substance. The drug discovery and development process requires close interaction among the different scientific discipline members for as many as 10—12 years. It is estimated that only 1 out of screened compounds is approved as a new drug.
Active pharmaceutical ingredient API : Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when used so, becomes an active ingredient of that pharmaceutical dosage form [ 3 ].
Human body is composed of a series of membrane barriers divided by aqueous-filled compartments. These membrane barriers are principally composed of the phospholipid bilayers resulting from the orientation of the lipids phospholipids, glycolipids, and cholesterol in the aqueous medium, which surround the cells and also form intracellular barriers around the organelles present in cells mitochondria, nucleus, etc.
Hence, the drug substance releases its hydration element and becomes hydrophobic. The drug disposition across the membrane depends on its lipophilicity and partition coefficient. Here, the protein binding plays an important role [ 4 , 5 ]. The polar molecules will be dissociated in an aqueous environment; thereby, the hydrophilicity arises and vice versa in the case of nonpolar molecules in a lipophilic environment.
Every component of an organic compound has a defined lipophilicity. Absorption and bile elimination rate are molecular weight dependent. Lower-molecular-weight compounds have better absorption and less bile excretion when compared to the higher-molecular-weight compounds.
Drugs with higher lipophilicity can be better absorbed from the intestine [ 5 , 6 ]. Biopharmaceutics is a major branch in pharmaceutical sciences which relates between the physicochemical properties of a drug in dosage form and the pharmacology, toxicology, or clinical response observed after its administration [ 7 ]. Drug efficacy and safety are dependent on the dosing regimen. The optimal dosage and dosing intervals can be quite different for different drugs. Moreover, for a single drug, the optimal dosage can be different widely between patients [ 8 ].
It is not sufficient to know what the drug does to the body; it is also crucial to know what the body does to the drug. The knowledge of the pharmacodynamic and pharmacokinetic properties of the drug and its metabolites in humans and animals is crucial to understand its different effects among species and for adjusting drug dosing [ 9 , 10 ].
The plasma concentration of the drug is the basic concept of pharmacokinetics. Based on protein binding of the drug, the concentration of free drug available in the circulation influences greatly the dose calculations.
The concentration of drug in the plasma is in equilibrium with some tissues in the body [ 11 ]. Blood is the transporter of many vital substances and nutrients for the entire body and thus contains many endogenous and exogenous compounds in different concentrations. Sample pretreatment is required for achieving sufficient sensitivity and selectivity to determine the active principle. Chemical assays of high quality which include adequate sensitivity, selectivity and reproducibility are essential for obtaining valuable data.
Bioanalysis is a subdiscipline of analytical chemistry covering the quantitative measurement drugs and their metabolites in biological systems. Various analytical instrument methods such as high-performance liquid chromatography HPLC or gas chromatography GC or ultra performance liquid chromatography UPLC with variety of detectors such as UV, fluorescent, diode array, flame ionization, electron capture and mass spectrometry, and capillary electrophoresis—mass spectrometry may be used.
Pharmacodynamics refers to the relationship between drug concentration at the site of action and the resulting effect, including the time course and intensity of therapeutic and its adverse effects. Studies are designed to investigate all primary and secondary effects related to the desired therapeutic effects, extensions of the therapeutic effect that might produce toxicity at higher doses, and effects related to interactions with other drugs.
In general, pharmacokinetic parameters are derived from the measurement of drug concentrations in blood or plasma [ 1 ].
Absorption studies generally involve serial determinations of drug concentration in blood and urine after dosing to indicate the rate and extent of absorption. Drug absorption refers to the passage of drug molecules from the site of administration into the circulation. Drug absorption requires that drugs cross one or more layers of cells and cell membranes. Solubility is manipulated mainly by the structure of the drug.
In general, solubility is inversely proportional to the number and type of lipophilic functions within the molecule and tightness of the crystal packing of the molecule. Solubility decreases when there is increase in crystal packing or lipophilicity. The concentration of drug in solution is the driving force of the membrane transfer of drug into the body, and low aqueous solubility often continues to present itself as a problem even after formulation improvements.
Biological factors: Permeation of the drug across the membrane, GI transit, site specificity, first-pass metabolism, metabolism in the liver, excretion as bile, excretion through bladder, and protein binding of drugs.
Pharmaceutical factors: Excipients, type of dosage forms, process of preparation, stability testing, and storage directions. Other factors: Solubility of the drug; partitioning properties; dissociation characteristics; salt formation; particle size, shape, volume, and its distribution; crystallinity; polymorphism; prodrugs; and stereotype and its formation [ 8 , 13 , 14 ]. Drugs may be either weak acids or bases that exist in both ionized and non-ionized forms in the body.
Drug in the non-ionized form is sufficiently soluble in membrane lipids and can cross cell membranes. The rate of absorption depends upon the ratio of the two forms at a particular site and is also a factor in distribution and elimination. The protonated form of a weak acid is non-ionized, whereas the protonated form of a weak base is ionized. The pKa is the negative log of the ionization constant, particular for each acidic or basic drug.
Protonated form predominates when the pH is less than the pKa, whereas nonprotonated form predominates when pH is greater than the pKa. In the stomach, with a pH of 1, weak acids and bases are highly protonated. Weak acids are absorbed without dissociation than weak base from the stomach and exactly opposite in the intestine where weak bases are absorbed readily than weakly acidic drugs. In intestine, weakly acidic drugs are also found to be absorbed even though they are ionized due to the large surface area [ 15 ].
Absorption takes place across the biological membrane by two methods. Lipid drugs are absorbed by transcellular mechanism where the drug distributes into the lipid core of the membrane which diffuses into the other side of the membrane. The solute may also diffuse across the cell membrane and enter into the circulation. Another mechanism is the paracellular absorption. The aqueous-filled pores in between the cells aid absorption of the drugs.
Water-soluble drugs are readily absorbed, but the molecule size of the particle plays an important role [ 5 , 12 ]. Drug absorption through transcellular and paracellular pathways is shown in Figure 1. The concentration gradient provides energy for the transportation of the drug across the membrane, and also partitioning of the drug in favor of the lipid membrane decides the quantity of the drug absorbed.
The unionized drug is absorbed markedly higher than the ionized form. It postulates that the flux goes from regions of high concentration to regions of low concentration, with a magnitude that is proportional to the concentration gradient, or in simplistic terms, the concept that a solute will move from a region of high concentration to a region of low concentration across a concentration gradient.
Active transport is the movement of molecules across the lipid cell membrane against concentration gradient, i. The absorption sites are at a specific place in the GIT. Active transport is usually associated with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. This active transport process uses chemical energy, such as from adenosine triphosphate ATP. These energy molecules are site specific — the drugs are transported at a particular site in the GIT, they are limited in number, and they act like a ferry service: it picks a molecule from the GIT, ferries across, leaves in the cytoplasm, and comes back to pick another molecule.
Endocytosis is an energy-using process by which cells absorb molecules such as proteins by engulfing them. It is used by large polar molecules that cannot pass through the hydrophobic plasma or cell membrane. The opposite process is exocytosis. Phagocytosis is a specific form of endocytosis involving the vascular internalization of solids such as bacteria by an organism and is therefore distinct from other forms of endocytosis such as the vesicular internalization of various liquids pinocytosis.
Phagocytosis is involved in the acquisition of nutrients for some cells. Pinocytosis, otherwise known as cell drinking, fluid endocytosis, and bulk-phase pinocytosis, is a mode of endocytosis in which small particles are brought into the cell, forming an invagination and then suspended within small vesicles [ 14 , 16 - 21 ].
Various types of endocytosis are shown in Figure 2. Various in vitro, in situ, and in vivo tools and techniques are used to characterize the absorption of drug substance to determine the rate and extent of absorption. Various models from low-throughput in situ rat model to high-throughput in silico models are used. Screening models for absorption such as human colon adenocarcinoma cell lines Caco-2 and HT are widely used; recently, MDCK cell line is used as an alternative one.
In vitro cell culture models have been utilized to assess the permeability and metabolism of drugs, to elucidate molecular mechanism of drug transport to provide information on pathways of drug degradation, and to explore the influence of structure in the absorption of new chemical entities. The cultured epithelial cells undergo enterocyte-like differentiation in culture and spontaneously differentiate into polarized columnar cells that are representative of the small intestine, with developed microvilli and polarized distribution of brush border enzymes.
When grown on plastic membrane, epithelial cells result in a confluent monolayer and therefore serve as a model to study drug absorption. Isolated mucosal cell suspensions have been used to study enzyme activity, drug transport, and cellular metabolism. The use of mucosal cells in drug absorption and transport studies is limited due to rapid autolysis. Isolation of brush border membrane vesicles has been used extensively to study mucosal uptake process especially to investigate factors that influence mucosal uptake without interference of intracellular metabolism.
Everted sac technique: To prepare everted sac, a small length of the intestine is excised, turned inside out, filled, and ligated at both ends. The sac is immersed in an oxygenated solution that contains a drug. The fluid inside the sac is assayed for the drug, and the rate of drug transfer across the membrane provides an estimate of drug permeability.
Intestinal rings: Prepared by excising a portion of the intestine, everting it over a glass road, and cutting it into rings approximately 30—50 mg. The rings are then incubated in an oxygenated culture media that contain a drug. At the end of the incubation, the tissues are extracted and the unchanged drug is measured. Intestinal ring preparation can be used to measure the rate of uptake and accumulation of a drug from the intestines. In this technique, the epithelium is mounted as a flat sheet between two chambers.
The solution on each side of the chamber is oxygenated and maintained at physiological temperature. The test drug and markers for volume fluctuation or tissue viability are placed in the chambers. Samples can be obtained from the serosal and mucosal chambers to study diffusion and permeability.
Perfused intestine—liver preparations [ 12 , 22 - 25 ]. The disposition of drug into the organs and tissues via circulation depends upon the nature of the drug. The more lipophilic the drug is, the better will be the distribution into the organs and tissues.
Pharmacokinetics and pharmacodynamics of propranolol in hypertensive patients after sublingual administration: systemic availability. Mansur, S. Avakian, R. Paula, H. Donzella, S. Santos and J. The bioavailability of propranolol depends on the degree of liver metabolism.
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If your institution subscribes to this resource, and you don't have a MyAccess Profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus. Please consult the latest official manual style if you have any questions regarding the format accuracy. Drugs are substances intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. Drugs are given in a variety of dosage forms or drug products such as solids tablets, capsules , semisolids ointments, creams , liquids, suspensions, emulsions, etc, for systemic or local therapeutic activity. Drug products can be considered to be drug delivery systems that release and deliver drug to the site of action such that they produce the desired therapeutic effect and are also designed specifically to meet the patient's needs including palatability, convenience, and safety. Drug product performance is defined as the release of the drug substance from the drug product either for local drug action or for drug absorption into the plasma for systemic therapeutic activity. Advances in pharmaceutical technology and manufacturing have focused on developing quality drug products that are safer, more effective, and more convenient for the patient.
Chapter 1: Introduction to Biopharmaceutics and Pharmacokinetics · Sections · Download Chapter PDF · Share · Get Citation · Tools · Clip.
If your institution subscribes to this resource, and you don't have a MyAccess Profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus. Please consult the latest official manual style if you have any questions regarding the format accuracy. Define drug product performance and biopharmaceutics. Define pharmacokinetics and describe how pharmacokinetics is related to pharmacodynamics and drug toxicity.
Lakshmana Prabu, T. Suriyaprakash, K. Ruckmani and R.
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Biopharmaceutics and pharmacokinetics are pharmaceutical disciplines useful to improve the Download chapter PDF Introduction.Auristela C. 19.05.2021 at 11:35
The therapeutic response of a drug is normally dependent on an adequate concentration of the drug being achieved and then maintained at the site or sites of action of the drug.