Pharmacokinetics (PK), also known as pharmacokinetics, is a discipline that studies the process of drugs in the body, including the changes in the absorption, distribution, metabolism and excretion of drugs and their metabolites over time, and applied kinetics A quantitative description of this process by principles and mathematical processing methods.
Pharmacokinetics is a discipline that originated in the West. Many literatures literally translate pharmacokinetics as “pharmacokinetics”. Pharmacokinetics is translated as “pharmacokinetics”, also known as “pharmacokinetics” or “pharmacokinetics” in the pharmacy terms published by the National Scientific and Technical Terms Review Committee. The “pharmacokinetics”, “pharmacokinetics” and “pharmacokinetics” in domestic publications are still used at the same time. Smith DA et al. believe that “pharmacokinetics” is a study of the time rules of absorption (A), distribution (D), metabolism (M) and excretion (E) of drugs (including foreign substances) in the organism Subject. It should be noted that ADME research is related to but not equivalent to pharmacokinetic research. In general, ADME research is included in PK research.
The drug enters the body from the site of administration to produce drug effects, and then is discharged from the body, during which it undergoes four basic processes of interaction, absorption, distribution, metabolism, and excretion, which is called the in vivo process of drugs. This process has a great influence on the onset time, effect intensity and duration of the drug. Drug metabolism and excretion are both the process of gradual disappearance of drugs in the body, collectively called elimination (elimination); drug distribution and elimination are collectively called disposition. If absorption, distribution, and excretion are only the migration of the drug in space, it is collectively called transportation. If the structure and properties of the drug change during this process, it is called biotransformation, and the product is called Metabolite (metabolite).
Pharmacokinetics
Our Preclinical Pharmacokinetics Department has a number of professionals with rich theoretical knowledge and experimental experience for experiment design, experiment implementation, bioanalysis and data analysis. Our Pharmacokinetics Lab has passed the GLP certification by NMPA. Following the guiding principles of ICH, NMPA and FDA. The lab offers in vivo and in vitro pharmacokinetic tests according to the needs of our clients and provide them with complete sets of pharmacokinetic evaluation and optimization services. Our acclaimed quality data collection and efficient experiment can meet our clients’ needs from early drug discovery to new drug filing.
Absorption refers to the process by which drugs enter the blood circulation from the site of administration. In addition to direct intravenous administration, the speed and amount of drug absorption are related to the route of drug administration, physical and chemical properties, and absorption environment.
Biofilm is a general term for the plasma membrane on the outside of the cell and the membranes of various organelles in the cell (such as nuclear membrane, mitochondrial membrane, endoplasmic reticulum membrane and lysosome membrane, etc.). The absorption, distribution, excretion and metabolism of drugs are closely related to the transport of substances across membranes. There are mainly three modes of drug transport across the membrane: passive transport, active transport and membrane dynamic transport. They have their own characteristics and are closely related to the pharmacokinetic characteristics of the drug.
Passive transport is the most important way of drug transport across the membrane. According to the concentration difference between the two sides of the membrane, the drug is transported from the side with high concentration to the opposite side with low concentration. This is also called forward concentration transport. The diffusion rate of drug transport across the membrane mainly depends on the molecular weight of the drug, fat solubility and the permeability of the biomembrane. The transport speed of passive transport is proportional to the concentration difference (concentration gradient) of the drug on both sides of the membrane. The larger the concentration gradient, the easier the diffusion. There is no competitive inhibition between the drugs transported by passive transport, and the transport stops when the drug concentration on both sides of the membrane reaches equilibrium.
Active transport refers to the process in which drugs rely on specific protein carriers (transporters) in the biofilm to transport from the low concentration or low potential side to the higher side, also known as countercurrent transport. The transport capacity of the transporter has a certain limit, that is, the transport process is saturated; two drugs transported by the same carrier can exhibit competitive inhibition. Certain transporters can excrete the substances entering the cells into the intestinal lumen, reducing the concentration of the substances in the cells and presenting an efflux pump phenomenon. This transport protein is mainly P-glycoprotein, and inhibiting the function of P-glycoprotein can reduce the outflow of substances into the cell. Clinically, when the function of P-glycoprotein is inhibited, it may cause drug interaction.
The transport of macromolecular substances is accompanied by membrane movement, which is called membrane transport. Membrane transport is divided into two situations: pinocytosis and exocytosis. Pinocytosis, also known as transcytosis, means that certain liquid proteins or macromolecular substances can enter the cell through the phagocytosis of small cells formed by the invagination of biological membranes. Such as Pituitrin powder, can be absorbed from the nasal mucosa. Exocytosis, also known as cell, refers to certain liquid macromolecular substances that can be transported from inside the cell to the outside of the cell, such as the release of glandular secretions and transmitters.
After oral administration of the drug, the drug is mainly absorbed from the mucosal epithelial cells of the gastrointestinal tract through passive transport. Because the absorption surface area in the stomach is small, and the residence time of the drug in the stomach is short, the absorption amount of many drugs in the stomach is small. There are villi on the surface of the small intestine, the absorption area is large, the intestinal peristalsis is fast, and the blood flow is large. Therefore, the main part of oral absorption of drugs is the small intestine. In addition to simple diffusion, absorption methods include active transport. After the drug is absorbed from the gastrointestinal tract, it must pass through the portal vein, enter the liver, and then enter the blood circulation.
Sublingual administration or rectal administration, the drug is absorbed through the oral cavity, rectum and colon mucosa. Although the absorption surface area is small, the blood supply in these parts is abundant, and the drug can be quickly absorbed into the blood circulation without passing through the liver first. Drugs that are easily destroyed in the gastrointestinal tract or rapidly metabolized in the liver can be administered by these two routes. Such as nitroglycerin for the treatment of angina pectoris and isoproterenol for the control of acute attacks of bronchial asthma can be administered sublingually.
There are many factors that affect the absorption of drugs in the gastrointestinal tract, such as drug dissolution and release rate, gastrointestinal pH, absorption area, gastrointestinal secretion and peristalsis, local blood flow and diet, etc., may affect the rate and extent of drug absorption. High pH is good for the absorption of weakly alkaline drugs, and low pH. It is good for the absorption of weakly acidic drugs; the pH of gastric juice is 0.9-1.5, and weakly acidic drugs can be absorbed in the stomach; the pH of the intestinal cavity is 4.8-8.2, and the intestines are healed The lower the pH is, the higher the pH is, and the weak acid and weak base drugs are easily dissolved and absorbed. The greater the surface area of the gastrointestinal tract and the richer the blood flow, the faster the drug absorption. The rate of gastrointestinal peristalsis can change the residence time of the drug in the gastrointestinal tract and the pH of the absorption environment to affect the absorption of the drug. Food may have a significant impact on drug absorption. For example, fat-soluble components in food can form complexes with drugs to affect drug absorption.
Injection administration includes intramuscular injection, subcutaneous injection and intravenous injection. The absorption speed of injection administration is generally faster than oral administration, and the bioavailability is higher. After administration, the drug first diffuses to the surrounding water-rich tissues, and then enters the blood circulation through the capillaries. The water solubility of the drug and the blood flow at the injection site affect the absorption rate of the drug during injection. Drugs with high water solubility are easy to diffuse in the injection site, increasing the absorption area, which is conducive to absorption; suspension absorption is slow and lasting. Some drugs are absorbed less quickly by injection, such as ampicillin, tetracycline, diazepam, and phenytoin. In injection sites with rich blood flow, such as skeletal muscle, the drug is absorbed quickly.
Intravenous administration has no absorption process, which can make 100% of the drug enter the human circulation. Therefore, the drug dosage is accurate and the effect is rapid. It is suitable for drugs with large drug volume, difficult to absorb or strong irritation, and used in emergencies, severe diseases and anesthesia. .
The transdermal drug delivery system (TDDS) includes patches, ointments, plasters, paints, aerosols, and the like. After being administered by skin application, smearing, spraying, etc., the drug mainly enters the dermis through the stratum corneum and epidermis, diffuses into the capillaries, and then enters the human circulation. Between the stratum corneum cells is a multilayer lipid bilayer formed by lipid molecules. The drug is transported in a passive diffusion mode mainly through the difference between the drug concentration on the skin surface and the drug concentration in the deep layers of the skin. In addition, a small amount of the drug is absorbed through accessory organs such as hair follicles, sebaceous glands and sweat glands. Transdermal administration can avoid the first pass effect of the drug and gastrointestinal inactivation, maintain a relatively constant absorption rate, and stabilize the blood drug concentration. After transdermal administration, the stratum corneum containing lipids in the skin is the biggest physiological obstacle that limits the absorption of drugs. Even with the use of penetration enhancement technology, the absorption rate of most drugs is still very small. Highly fat-soluble drugs are easily absorbed through the skin.
The nasal mucosa has a large number of fine villi, which can significantly increase the effective surface area for drug absorption. There are large and many capillaries under the nasal epithelial cells, which can allow body fluids to quickly pass through the blood vessel wall into the human body to circulate, so the drug is absorbed quickly and the degree of absorption is high. The absorption rate of these drugs is even comparable to that of injections. In addition, studies have found that the nasal mucosa is an ideal route for compounds to enter the central nervous system and peripheral circulatory system, but the transport mechanism of this route is still unclear. The drug is absorbed from the nasal cavity and enters the systemic circulation without passing through the portal vein, which can avoid the liver first pass effect.
The nasal mucosa has a lipid-like structure, and the absorption of drugs in the nasal mucosa is mainly a passive diffusion process. Therefore, fat-soluble drugs are easily absorbed, while water-soluble drugs are poorly absorbed. Due to the low barrier function of the nasal mucosa and the richness of blood vessels, some dissociated drugs can also be absorbed. The absorption of the nasal mucosa is closely related to the molecular weight, the larger the molecular weight, the worse the absorption. Circular proteins and peptides are easier to absorb than linear ones. The nasal mucosa is negatively charged, so positively charged drugs can easily penetrate. The pH affects the dissociation of the drug. The undissociated type has the best absorption, the partially dissociated type also has absorption, and the completely dissociated type has poor absorption. The mucous cilia in the nasal cavity remove the drug from the turbinate to the nasopharynx, which greatly shortens the contact time between the drug and the adsorption surface, and affects the absorption and bioavailability of the drug.
After inhaled administration, the absorption of the drug in the lungs proceeds in the alveoli. It is estimated that the number of alveoli is 300 to 400 million, and the total surface area of the alveoli is 200 m2, which is very close to the effective absorption surface of the small intestine. The alveolar wall is composed of a single layer of epithelial cells and is closely connected to the capillaries. The thickness from the absorption surface to the capillary wall is only 0.5 to 1 μm (40 μm for the small intestine and 150 μm for the skin). The total surface area of these capillaries reaches 90 m2, the blood flow is very rich. Surface active substances (mainly phospholipids) are distributed on the surface of alveoli. The anatomical structure of the lung determines that the absorption of drugs in the lungs is very rapid, and the drugs can directly enter the systemic circulation without being affected by the first pass effect of the liver.
Alveolar epithelial cells are lipid membranes, and the absorption of drugs in the lungs is a passive diffusion process. The biggest factor affecting absorption is the fat solubility of the drug, but the barrier effect of the alveoli to water-soluble drugs is much lower than that of other parts. Another influencing factor is the molecular weight of the drug. Small molecules are absorbed quickly, while large molecules are relatively difficult to absorb. The deposition and loss of the drug in various parts of the respiratory tract results in the percentage of reaching the alveoli is not high enough.
The process of drug transport from blood to various tissues and organs is called distribution. The distribution of most drugs in the body is uneven, which mainly depends on the binding rate of the drug and plasma protein, the blood flow of each organ, the affinity between the drug and the tissue, the pH of the body fluid, the physical and chemical properties of the drug, and the blood-brain barrier. The distribution of the drug in the body not only affects the storage and elimination rate of the drug, but also affects the efficacy and toxicity.
After the drug enters the blood, it will combine with the plasma components to varying degrees and become a combined drug. The unbound free drug enters the tissue outside the tissue through the endothelial cell layer of the capillary in different ways, and then enters the tissue cell through the tissue cell membrane, and sometimes combines with the intracellular components to complete the distribution process. The above steps are all reversible processes.
The distribution of drugs has obvious regularity. The drug is first distributed to tissues and organs with large blood flow, and then transferred to tissues and organs with small blood flow. This phenomenon is called redistribution. The distribution of drugs in the body is selective, and most of them are unevenly distributed. After a period of time after administration, the drug concentration in blood and tissues and organs reach a relative balance. At this time, the drug concentration level in plasma can indirectly reflect the drug concentration level of the target organ.
Systemic circulation includes blood circulation and lymphatic circulation. Since the blood flow rate is 200 to 500 times faster than that of the lymph fluid, the distribution of drugs in the body is mainly completed by the blood system, but the transport of drugs in the lymph system is also of great significance. Some drugs must rely on the delivery of the lymphatic system, and some diseases (immune system diseases, inflammation and cancer metastasis) require the delivery of drugs to the lymphatic system. The lymphatic system can also protect the drugs from the metabolic destruction of the liver. The lymphatic system transport of drugs varies with the method of administration, including the transport of drugs from the blood, interstitial spaces, and digestive tract to the lymphatic system. When the drug is administered intravascularly, the drug needs to diffuse into the lymphatic capillaries through the interstitial fluid; when the drug is administered in the lymphatic vessel, all the drug enters the lymphatic system; when the drug is administered in the interstitial space, the drug is transported to the blood vessels and lymph vessels respectively; After administration to the nasal mucosa or skin, the drug penetrates the epithelial cells of the administration site and enters the blood and lymph system respectively.
Drugs in the blood must pass through the capillary walls and lymphatic capillaries to enter the lymphatic system. Because the capillary wall has a small pore size, it becomes the main barrier. In addition, the distribution density and structure of blood vessels and lymphatic vessels in various tissues will cause differences in drug delivery in the lymphatic system. The transport of drugs from the blood to the lymph is almost a passive diffusion process, so the drug concentration in the lymph will not be higher than the blood drug concentration. The plasma protein binding rate of the drug also affects the transport process. The blood pressure of the capillary, the static pressure of the tissue fluid, and the colloidal osmotic pressure of the plasma and tissue fluid also have a certain impact.
When interstitial administration such as intramuscular or subcutaneous injection or intraorgan or intratumor injection, the drug has two transport routes: capillary and lymphatic capillaries. At this time, the nature of the drug, especially the size of the molecular weight and the permeability of the tube wall determine the transport route of the drug. Drug molecules with a molecular weight of less than 5kDa can be entered in both ways, but since the blood flow is much larger than the lymph flow, almost all of them are apparently transported by blood. On the contrary, macromolecular drugs with a molecular weight greater than 5 kDa have an increasing tropism to the lymphatic system as the molecular weight increases. In order to increase the tropism of the drug to the lymph, the drug molecules can be formed into various polymer complexes, or made into water-in-oil (W/O) emulsions, liposomes, microspheres, etc.
After being administered orally, digestive tract, rectum, oral cavity, nasal cavity, skin and other places, the drugs pass through barriers such as mucosal epithelial cells, stratum corneum and squamous epithelial cells, and then transport to blood vessels and lymphatic vessels. Therefore, in principle, the lymphatic transport of the drug is basically the same as the drug delivery from the interstitial space. However, due to the barrier during absorption, the transport of drugs to the lymphatic system is restricted compared with injection, and non-fat-soluble drugs or polymer drugs can hardly pass through the barrier freely. Among the various routes of administration, the most studied is the absorption of drugs in the digestive tract, especially the absorption of drugs in the small intestine.
Plasma protein binding rate
There are 6% to 8% of various proteins in plasma, among which albumin and α1-acid glycoprotein are the main proteins that bind to drugs. The binding rate of drugs and plasma proteins is one of the important factors that determine the distribution of drugs in the body. Some drugs are reversibly bound to plasma proteins. The bound drugs cannot be transported across the membrane due to their increased relative molecular weight and have no biological effects temporarily. They are temporarily stored in the blood. Only free drugs can be transported to the site of action to produce biological effects. When the free drug in the blood is transported and metabolized to reduce the concentration, the bound drug can be transformed into the free drug again, and the two are in dynamic equilibrium. The plasma protein binding rate of various drugs is different. When the blood drug concentration is too high and the plasma protein binding reaches saturation, the free drug in the plasma increases suddenly, which can cause enhanced drug efficacy and even toxic reactions.
Organize blood flow
The blood flow distribution in the organs of the human body is the liver the most, followed by the kidney, brain, and heart. These organs are rich in blood vessels and have a large blood flow. After the drug is absorbed, it can quickly reach a higher concentration in these organs, and then it may redistribute to the tissues with low blood flow.
Cell and capillary membrane permeability
To enter the tissues and organs, the drug must first pass through the blood vessel wall (epithelial cell membrane), and finally penetrate the tissue cell membrane. The cell membrane is a protein-containing phospholipid bilayer, and the mechanism of drug penetration through the cell is consistent with the transmembrane transport mechanism. Drugs generally pass through cell membranes by passive diffusion, and undissociated drugs and fat-soluble drugs are easier to pass. That is, the pKa and oil/water partition coefficient of the drug can affect its permeability to the cell membrane.
Combine with tissue cell components
In addition to the effects of plasma protein binding on the distribution of drugs in the body, there are also many components in tissue cells that can be combined with drugs to affect drug distribution, such as proteins, fats, enzymes, and mucopolysaccharides and other high-molecular substances. Because the conjugate does not easily leak out of the cell membrane, the concentration of the drug that is highly bound to the tissue components in the tissue is higher than the concentration of the free drug in the plasma. For example, iodine is mainly concentrated in the thyroid; calcium is deposited in the bones; heavy metals such as mercury, arsenic, and antimony and metalloids are more distributed in the liver and kidneys, which can damage these organs when poisoned. Sometimes the drugs are distributed to some tissues that are not the parts where they exert their effects. For example, thiopental sodium is redistributed to adipose tissue; lead is deposited in bone tissue.
Body fluid pH and physical and chemical properties of drugs
Under physiological conditions, the pH of the intracellular fluid is about 7.0, and the pH of the extracellular fluid is about 7.4. Weakly acidic drugs dissociate more in the more alkaline extracellular fluid and are easily transported from the cell to the outside of the cell. On the contrary, weakly basic drugs have a slightly higher concentration in the cell.
When the plasma protein binding rate of the drug is high, it means that the free drug that can be freely transported to various tissues and organs in the body will be greatly reduced. In addition, when combined medications or other reasons inhibit this protein binding process, the concentration of free drugs may increase rapidly. Therefore, the combination of drugs and proteins will significantly affect the kinetic process of drug distribution and elimination, reduce the strength of the drug at the target site, and change the metabolism and excretion process of the drug.
In the process of new drug development, the comparison of animal and human plasma protein binding rates plays an important role in predicting and explaining the correlation between animal and human effects and toxicity. Generally, for drugs with a protein binding rate higher than 90%, in vitro drug competition binding tests are required, that is, drugs with high protein binding rates that may be used clinically are selected to investigate the effect on the protein binding rate of the drug under study, which is a follow-up clinical Provide reference for development and clinical application.
While the drug is absorbed and distributed in the body, the chemical structure is changed under the action of drug metabolizing enzymes, which is called biotransformation. Most drugs lose pharmacological activity after biotransformation, which is called inactivation; a small number of inactive drugs are transformed into active drugs or weakly active drugs become active drugs, which is called activation. Certain water-soluble drugs can be excreted through the kidneys without conversion in the body. However, most fat-soluble drugs are transformed into dissociated or highly water-soluble metabolites in the body, reducing their reabsorption by the renal tubules, and then being excreted by the kidneys. The ultimate goal of transformation is to facilitate the excretion of drugs from the body.
The location of drug metabolism in the body is mainly related to the distribution of drug-metabolizing enzymes and local tissue blood flow. The liver is the main metabolic organ for most drugs due to its high blood flow and most metabolic enzymes. Metabolic enzymes mainly exist in liver cell microsomes, which are cell-like structures formed by the endoplasmic reticulum. In addition to being metabolized in the liver, some drugs can be metabolized in the digestive tract, kidney, lung, skin, brain, nasal mucosa and other parts or metabolized by intestinal bacteria.
The digestive tract is the most common site of extrahepatic metabolism. Certain drugs can bind to a large number of enzymes present in intestinal epithelial cells, resulting in reduced bioavailability. For example, the blood concentration of salicylamide when administered orally is much smaller than when the same dose is administered intravenously. The reason is that more than 60% of the drug undergoes a binding reaction in the mucosa of the digestive tract.
The intestinal flora may have a significant impact on the metabolism of drugs that stay in the intestine for a long time or are excreted through bile. The flora in the intestines can cause drugs to undergo reactions such as reduction, hydrolysis, acetylation, dealkylation, deCO2, and formation of nitrosamine and sulfuric acid conjugates. The metabolites of some drugs enter the intestines with bile and are converted into prototype drugs under the action of the flora and then reabsorbed, which prolongs the action time of the drugs. Sulfasalazine is a prodrug. After oral administration, a small part of it is absorbed in the stomach and upper intestine, and most of it enters the lower intestine. Under the action of intestinal microorganisms, the diazonium bond is broken and decomposed into 5-aminosalicylic acid. And sulfapyridine.
The kidney is distributed with cytochrome P450 monooxygenase and prostaglandin peroxidase synthase. The activity of glutathione S-transferase in rat kidney is higher, which is 60% of liver activity; it is 30% in guinea pig and 26% in rabbit.
The concentration of enzymes related to drug metabolism in the lungs is very low, but due to the large blood flow in the lungs, they play a non-negligible role in drug metabolism, but they are still significantly weaker than the liver. Cytochrome P450 monooxidase mainly exists in bronchial epithelial lara cells.
After oral medication is absorbed in the gastrointestinal tract, it reaches the liver via the portal vein. Some drugs are easily metabolized and inactivated when they pass through the intestinal mucosa and liver. When they pass through the liver for the first time, some of them are destroyed, reducing the effective amount into the blood circulation and reducing the efficacy of the drug. This phenomenon is called the first pass effect. Nitroglycerin can inactivate about 90% through the first pass effect, so it has poor oral efficacy and requires sublingual administration. Drugs with obvious first pass effects include chlorpromazine, aspirin, pethidine, propranolol, clonidine, lidocaine and so on. When the route of administration is changed, the absorption, distribution, and excretion of the drug will also change, and attention should be paid to the difference in dosages for different routes of administration.
The metabolic process of drugs in the body can be divided into two phases.
Phase I reaction, namely oxidation, reduction or hydrolysis, is the introduction or exposure of polar groups in the structure of the drug under the action of some enzymes, such as the production of carbonyl, carboxyl, sulfhydryl, and amino groups. This reaction inactivates the pharmacological activity of most drugs, but there are also a few drugs that are activated to enhance their effects, and even form toxic metabolites. The types of oxidation include sulfur oxidation, nitrogen oxidation, epoxidation, amine oxidation, alkylene oxidation, alcohol oxidation, aldehyde oxidation, purine oxidation, hydroxylation, dealkylation, desulfurization, dehalogenation, deamine and so on. The types of reduction include nitro reduction, carbonyl reduction, azo reduction, aldehyde reduction and so on. The types of hydrolysis include ester bond hydrolysis, acyl bond hydrolysis, glycoside hydrolysis and so on.
Phase II reaction is the binding reaction. It is the polar group of the prototype drug or its metabolites, which is covalently bonded to endogenous substances such as glucuronic acid, sulfuric acid, glycine, and glutathione under the action of enzymes. , To produce metabolites with high water solubility and strong polarity, which are easily excreted from the body. The types of binding include glucuronic acid, glycine, taurine, glutamine, glutathione, sulfuric acid, methyl, acetyl, etc.
Drug metabolizing enzymes are divided into two categories, namely specific enzymes and non-specific enzymes. Specific enzymes are specific, such as cholinesterase and monoamine oxidase, which convert acetylcholine and monoamine drugs, respectively. Non-specific enzymes mainly refer to the mixed function oxidase (MFO) present in liver cell microsomes, referred to as liver drug enzymes. The enzyme system is composed of three parts: ①hemoglobin, including cytochrome P450 and b5; ②flavin proteins, including reduced coenzyme Ⅱ-cytochrome P450 reductase, reduced coenzyme cytochrome b5-reductase; ③phospholipids , Mainly phosphatidylcholine. Similar microsomal metabolic enzyme systems also exist in the small intestinal mucosa, kidney, and adrenal cortex cells.
Liver drug enzyme has the following characteristics: ① low selectivity, it can catalyze a variety of drug reactions; ② large variability, affected by heredity, age, nutritional status, body state, disease, individual differences; ③ vulnerable to activity The activity may increase or decrease under the influence of many factors. Drugs that can enhance liver drug enzyme activity are called enzyme inducers; drugs that can reduce liver drug enzyme activity are called enzyme inhibitors. For drugs that rely on the metabolism of liver drug enzymes, their metabolic rate and extent may be significantly affected by the induction or inhibition of liver drug enzymes. If the inducer causes an increase in enzyme activity, it may accelerate the metabolism of the drug itself or other drugs.
Cytochrome P450 is the most critical enzyme in the phase I metabolism of drugs. Studies have found that there are at least 8 cytochrome isoenzyme families in animals and humans, such as CYP1, CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, CYP3, CYP4, etc., among which CYP3A subfamily is the most abundant cytochrome in humans Enzyme. The metabolism of different drugs may be responsible for different isoenzymes. Due to genetic and environmental factors, the levels and activities of P450 isoenzymes vary among individuals. Studies have found that CYP2D6, CYPlA2, CYP2C9, and CYP2C19 equivalent enzymes have genetic polymorphisms, which are related to human fast and slow metabolism, and there are ethnic differences. For example, CYP2C19 polymorphism makes the frequency of slow metabolizers in the population appear: white People are 3%, Asians are 15%-25%, and blacks are 4%-7%.
There are many factors that affect drug metabolism, but they can all be manifested as an acceleration or a slowdown in metabolism. If the metabolism of the drug is accelerated, the effective therapeutic effect may not be achieved; the slowing of the metabolism may cause the concentration of the drug in the body to increase. Repeated medication may cause accumulation and cause toxicity. Understanding the factors affecting drug metabolism is of great significance for how to give full play to the efficacy of drugs and reduce or inhibit the toxic side effects of drugs according to the specific conditions of the patient’s pathology, physiology, and drug characteristics.
People of different ages may have significant differences in the metabolism of drugs. For example, the metabolic function of children may not be fully developed, while the metabolic function of the elderly gradually decreases. The activity of drug-metabolizing enzymes in fetuses and newborns is low or even lacks in activity. Therefore, when fetuses and newborns take drugs, in most cases, not only the drug is effective, but also prone to toxicity. For example, the liver drug-enzyme system of the newborn’s liver is not fully developed, causing the metabolism of chloramphenicol to be significantly slowed down and the half-life is significantly prolonged, which may lead to gray baby syndrome. Studies have found that the functions of related enzymes such as hydroxylation reaction, N-demethylation reaction, O-dealkylation reaction and nitro reduction reaction in neonatal liver are imperfect.
In the elderly, the activity of some metabolic enzymes is reduced or the endogenous cofactors are reduced, which slows down the metabolism of some drugs, such as significantly prolonging the half-life of diazepam. Decreased hepatic blood flow and functional hepatocytes in the elderly are also one of the important reasons that slow down drug metabolism.
There are gender differences in the metabolism of some drugs. For example, in rats, there are gender differences in the liver drug enzyme activities of some drugs. For example, the metabolism of phenobarbital and nicotinamide in male rats is fast, so these drugs have less efficacy and toxicity in male rats; Glucuronic acid binding, acetylation, and hydrolysis reactions in mice were also found to have gender differences. A few clinical studies have also found that the human body has similar gender-related metabolic differences.
There may be big differences in the metabolism of the same drug in different animal species, not only in the metabolic rate, but more importantly, there are differences in the types of metabolites. Therefore, when using animal data to extrapolate to humans, full consideration should be given to the differences in the metabolism of drugs between the experimental animals and humans used. If the metabolism of the drug in laboratory animals and humans is similar, it is relatively safe to use animal data to predict the efficacy and toxicity of humans. On the contrary, if the metabolism of the drug is very different between experimental animals and humans, especially the types of metabolites, the reliability of using animal data to predict human response is less. Therefore, from the perspective of the development of new drugs, it is necessary to arrange animal and human pharmacokinetic studies as soon as possible, compare the results, identify relevant animals, conduct non-clinical studies on effectiveness and safety, and improve non-clinical studies in clinical research predictions The reliability. At present, the US FDA has encouraged and required R&D companies to obtain animal and human metabolism research data as soon as possible in order to improve the purpose and reliability of non-clinical research.
It is known that there are obvious individual differences in drug metabolism in the population, and the reasons for this difference are genetic differences and non-genetic differences. Genetic differences are mainly caused by race or family genetic characteristics. Studies have shown that the nature or activity of liver drug enzymes is determined by genetic factors. Non-genetic differences are mainly caused by age, gender, liver function, time cycle rhythm of drug metabolism, body temperature, nutritional status, and environmental factors (such as exposure to drug enzyme inducers or inhibitors). Because the factors that cause non-genetic metabolic differences are more complex, non-genetic differences are sometimes very large, and can even exceed ethnic differences. For example, when desipramine is used in the same population, the steady-state blood concentration of different individuals can differ by more than 30 times.
Diseases may affect the function of metabolic organs. The liver is the main metabolic organ. Disorders of liver function may reduce the ability of drug metabolism, increase the blood drug concentration and prolong the half-life. Therefore, some drugs require dose adjustment in patients with low liver function.
The influence of diet on drug metabolism mainly depends on the nutrients such as sugar, protein, fat, trace elements and vitamins in the diet. For example, the lack of linoleic acid or choline in the food may affect the production of phospholipids in the microsomes, making the liver drug enzymes unable to adapt to increase; when protein is lacking, it can slow down the differentiation of liver cells and reduce the activity of liver drug enzymes.
Excretion refers to the process by which drugs are excreted from the body in the form of prototypes or metabolites through excretory or secretory organs. Most drugs and their metabolites are excreted by passive transport, and a few are excreted by active transport, such as penicillin. The body’s excretion or secretion organs are mainly kidneys, followed by bile ducts, intestines, salivary glands, breasts, sweat glands, lungs and so on.
The kidney is the main excretion organ. Most free drugs and their metabolites can be filtered through the glomerulus and enter the renal tubules for excretion; a few drugs are actively secreted from the proximal tubules to the renal tubules for excretion. There are three types of excretion in the kidneys: glomerular filtration, tubular secretion and tubular reabsorption.
Glomerular filtration
The basement membrane of the glomerular capillary network is more permeable and has a higher filtration pressure, allowing substances with a molecular weight of less than 20 kDa to pass. Therefore, in addition to blood cell components, larger molecular substances and drugs bound to plasma proteins, most free drugs and metabolites can be filtered and then enter the renal tubules. Highly fat-soluble, low-polarity, non-dissociated drugs and metabolites can be reabsorbed into the blood through renal tubular epithelial cells. If the pH of urine is changed, the degree of dissociation of weakly acidic or weakly basic drugs can be changed, thereby changing the degree of drug reabsorption. Such as taking alkaline drugs to alkalize urine, increase the dissociation degree of phenobarbital and salicylic acid, reduce reabsorption, increase excretion rate, and detoxify.
Renal tubular secretion
The secretion of renal tubules is an active transport process, and the drug follows a reversible concentration gradient from capillaries through the tubule membrane to the tubules. Renal tubular epithelial cells have two types of transport systems, organic acid and organic base transport systems, which transport weakly acidic drugs and weakly basic drugs, respectively. When two types of drugs with the same secretion mechanism are used in combination, they are transported by the same carrier and competitively inhibited, which slows down the excretion of drugs. Probenecid is a weak organic acid, which can compete to inhibit the secretion of penicillin G and other penicillin drugs in the renal tubules, prolonging the retention time of the drugs in the body.
Renal tubule reabsorption
After the free drug is filtered from the glomerulus, it is secreted and reabsorbed through the renal tubules. The renal tubular reabsorption of most drugs is passive transport, but compounds containing lithium and fluorine and uric acid are reabsorbed through active transport. The renal tubule membrane facilitates the passage of fat-soluble drugs. It is difficult to reabsorb low-fat-soluble drugs or ionic drugs. The reabsorption of weak acid or weakly basic drugs depends on the pH of the renal tubule fluid.
Some drugs can excrete bile through the liver, flow into the intestinal cavity from the bile, and then be excreted with feces. There are three forms of elimination of drugs from bile: prototype drugs, glucuronic acid conjugates and glutathione conjugates. The process of bile excretion includes two processes, passive transport and active transport. The passive transport of small molecule drugs in the blood to the bile is to diffuse through the pores of the cell membrane. As the drug molecules increase, the concentration in the bile decreases.
The concentration of some drugs or their metabolites in the bile is significantly higher than the concentration in the blood, which can be actively transported and excreted. At present, it is known that there are at least five active transport systems in liver cells, including organic acids, organic bases, neutral compounds (such as cardiac glycosides, steroid drugs), cholic acid and bile salts, and heavy metal transport systems. The active transport process is saturated, and drugs using the same transport system can produce competitive inhibition.
Some drugs are secreted into the intestine with bile, can be absorbed by intestinal mucosal epithelial cells, and re-enter the human circulation via the portal vein. This circulation process among the small intestine, liver, and bile is called enterohepatic circulation. For example, the drug is secreted into the bile after binding with glucuronic acid in liver cells, and then excreted into the intestine. The free drug produced after hydrolysis is reabsorbed into the systemic circulation, thereby prolonging the half-life of the drug, such as digitoxin, Digoxin, Diazepam, etc.
After oral administration of the drug, the unabsorbed part of the intestine, the part excreted into the intestine with bile, and the part secreted into the intestine by the intestinal mucosa, can be excreted in the feces through the intestine.
Some medicines can be excreted from breast milk, saliva, tears or sweat. Since milk is acidic and rich in lipids, drugs with strong fat-soluble properties and weakly alkaline drugs are easily excreted in breast milk and affect infants, such as morphine and chloramphenicol. Certain drugs can be excreted from saliva, and the excretion is related to the blood concentration. At present, some drugs can be detected by saliva concentration. Volatile drugs are mainly discharged from the lungs, such as inhaled anesthetics. Certain drugs can also be excreted from sweat glands, such as rifampicin which can stain clothes red. Trace metal elements can be excreted from the hair and have certain diagnostic value. If the drugs excreted through the above routes are non-dissociated drugs, the degree of excretion depends on the amount of glandular epithelial cells diffused into the secretion fluid, and the degree of excretion of dissociated drugs depends on pH.
Medicilon’s Drug ADME/PK Assays Services
Factors Affecting Pharmacokinetics of Drugs
High Throughput ADME Study of New Drug Discovery
Drug absorption, distribution, metabolism and excretion (pharmacokinetics)
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