Pharmacokinetics

Author: Tu Xide
Editor-in-Chief: Tu Xide
Publisher:
Publishing Date: 1998-01-01
Features:
Content Summary
This book is written by the editor based on more than ten years of teaching experience, incorporating new theories, methods, and research findings in the field of biopharmaceutics in recent years. The book is divided into eight chapters, providing a comprehensive introduction to the processes of drugs in the body, the influence of physicochemical properties and dosage forms on the bioactivity of drugs, and the relationship between different dosage forms and the same administration route on pharmacological effects. It also discusses the time-dependent changes in blood drug concentrations in the body based on pharmacokinetic principles, thereby providing a scientific basis for the correct evaluation of drug quality and rational clinical drug use. This book serves as a relatively up-to-date reference for modern biopharmaceutics teaching and can also be used as a reference book for scientific research, medical, and testing personnel.
Excerpt:
The rate of drug transport is determined by the physicochemical properties of the drug, the properties of the membrane itself, and the concentration gradient. The driving force for drug diffusion is the drug concentration gradient between the gastrointestinal fluid and blood. Drug molecules move from one side of the membrane to the other at the side with higher concentration. The drug concentration gradient between the gastrointestinal tract and blood always exists and determines the drug transport. Passive absorption follows first-order kinetics, where the transport rate is proportional to the drug concentration at the absorption site. That is, when the concentration is doubled, the transport rate also doubles, as shown in Figure 2-3. Fick's diffusion law describes the mechanism of membrane diffusion from a mathematical perspective. Figure 2-4 shows its equation and variables. Fick's law states that the absorption rate is proportional to the membrane surface area (A), the drug distribution coefficient (Km/f), and the diffusion coefficient (D). According to Fick's law, larger areas (such as the small intestine) are the best absorption sites, and drugs are absorbed fastest in the upper small intestine. Drugs with higher lipophilicity have larger distribution coefficients and are absorbed more rapidly. The distribution coefficient of organic weak acids or weakly basic drugs varies with the pH environment in which the drug is present, and pH can also change the drug's diffusion coefficient. The diffusion coefficient of a drug determines its ability to pass through the membrane via diffusion, and for a specific drug, it is a constant. The gastrointestinal area and thickness in animals (such as humans) can be relatively considered as constants. Therefore, for the human gastrointestinal system and a specific drug, the aforementioned Km/f, A, and D/h can be combined into a mixed constant (K), known as the permeability coefficient. During drug absorption, the force driving drug diffusion through the membrane is always present because the drug concentration in the blood is relatively lower compared to the gastrointestinal tract. The volume of liquid in the gastrointestinal tract is very small compared to the circulatory system, so when the drug enters the bloodstream, it is rapidly diluted. Binding and secretion processes also continuously reduce the concentration of free drugs. If the drug concentration in the gastrointestinal tract (CG1T) is much higher than the blood drug concentration (CB), the CB term in the Fick's equation can be omitted. Thus, the final equation can be written as dc/dt = KCG1T. This equation describes a first-order absorption kinetics process, indicating that the drug absorption rate depends on the drug concentration in the gastrointestinal tract, and the drug concentration is influenced by the administered dose, as shown in Figure 2-5 [2].
2. Carrier Transport
In carrier transport, chemical carriers on the membrane bind to the drug and transport it to the other side of the membrane, where it separates from the drug, as shown in Figure 2-1. Carrier transport is divided into active transport and facilitated transport. Active transport is particularly important for drug transport, where the biological membrane plays an active role. Carrier proteins on the membrane temporarily bind to drug molecules, promoting their translocation across the membrane. Active transport requires chemical energy, allowing drug molecules to move against the concentration gradient from the low-concentration side to the high-concentration side. The main difference between active transport and passive diffusion is that active transport is saturable, meaning that when the dose is significantly increased, the absorption rate does not necessarily increase, as shown in Figure 2-3. In passive diffusion, the drug absorption rate increases with increasing concentration, whereas in active transport, when the absorption rate reaches saturation, further increases in drug concentration do not increase the absorption rate. Active transport occurs at specific absorption sites in the small intestine, and carrier proteins are selective. Drugs with similar structures often compete for carrier proteins on the membrane surface when they coexist. Na?, K?, I?, monosaccharides, amino acids, and certain water-soluble vitamins (such as vitamin B1, vitamin B2, vitamin B6, and niacin) as well as anticancer drugs like 5-fluorouracil and methyl dopa are absorbed through active transport. Facilitated transport is another carrier transport system that is similar to active transport but does not require energy and cannot move against the concentration gradient. The absorption of vitamin B12 in the gastrointestinal tract is an example of this transport system. It first binds to a factor in the gastric wall to form a complex, which then binds to a specific carrier protein for absorption.