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Pharmacokinetic (Pharmacokinetic) is a subject that quantitatively studies the absorption, distribution, metabolism and excretion of drugs in organisms, and uses mathematical principles and methods to explain the laws of changes in blood drug concentration over time.
According to reports, over 80% of investigational new drugs fail during development because of unsatisfactory absorption, distribution, metabolism, and excretion (ADME) characteristics. The ADME research can greatly impact clinical success, and early assessment of ADME characteristics has real value in improving the drug discovery and development process.
In the drug discovery stage, scientists provide new chemical entities for evaluation in various pharmacology and toxicology screens;
In the preclinical drug development stage, scientists provide a more refined evaluation of safety and efficacy for the preparation of the IND.
What is ADME?
It is the process by which a the drug enters the bloodstream from the site of administration through the biofilm. When taken orally, it must first pass out of the gastrointestinal tract and be delivered to the liver via the portal vein (the portal vein conducts blood from the digestive system, spleen, pancreas, and gallbladder to the liver). The drug and its metabolites are then available to move into the liver, and from the liver to the blood, where they are then distributed throughout the body by arterial circulation.
Digestive tract (oral administration, oral cavity, stomach, small intestine, large intestine), respiratory tract (nasal administration, lung), muscle (intramuscular injection), mucosa (suppository).
Different absorption sites, the degree and speed of drug absorption, there are differences (intravenous injection, intramuscular injection; Subcutaneous administration, oral.)
Commonality: Drugs are absorbed through biofilms.
Passive diffusion: diffusion rate is proportional to concentration gradient;No specificity;Unsaturation;The drug molecule must have a suitable lipid water partition coefficient. Most chemical drugs are absorbed by passive diffusion.
Membrane pore diffusion: substances with a molecular weight less than 100.
Easy diffusion: the involvement of transport carriers, saturation, and specificity; But you need a certain concentration gradient. For For example, glucose is absorbed by cells, and methotrexate and VB12 are absorbed by the small intestine.
Active transport: diffusion rate is independent of concentration gradient; It has structural specificity (essential nutritional molecules such as amino acids can be used as carriers of drug transport) and saturation; It is not necessary to have a certain fat-water distribution coefficient;It’s an energy-consuming process.
Ion pair transport: Strongly ionizing compounds such as sulfonates or quaternary ammonium salts combine with endogenous substances to form charge-neutral ion pairs, which are then transported through lipid membranes by passive diffusion.
Pinocytosis: fat, oil droplets, proteins, etc.Cell receptor mediated.
First pass effect: drugs absorbed from the small intestine pass through the portal vein to the liver, where they have metabolized
Enterohepatic circulation: drugs in the liver are secreted by bile to the gallbladder, from the gallbladder to the small intestine, and finally absorbed in the small intestine through the portal vein to the liver.
Water is the carrier of drug transport and the medium in the body is water. The drug must have a certain water solubility at the absorption site and be in a state of dissolution before it can be absorbed. Therefore, the drug is required to have certain water solubility.
Polarity (the introduction of polar groups can increase water solubility), crystal type (the influence of drug bioavailability has received more and more attention), melting point affect the solubility, thereby affecting drug absorption and bioavailability.
The structure of the double lipid layer of the cell membrane requires certain lipid solubility of the drug to penetrate the cell membrane. In (certain lipid solubility), out (certain water solubility).
Esterification of easily dissociated groups such as carboxyl groups.
Through the modification of chemical structure, the introduction of lipid-soluble groups or side chains can improve the lipid solubility of drugs, promote drug absorption and improve bioavailability.
Drugs can only pass through biofilms in molecular form.
The biofilm itself has an electric charge, which attracts each other.Repel each other: can’t get in.
Ions hydrate and drug molecules increase in size and cannot pass through biofilm micropores.
Therefore, the greater the degree of dissociation, the worse the absorption.
The dissociation degree is related to the dissociation constant of the drug and the pH of the absorbed site. The dissociation degree and absorption degree of the same drug in different parts are different. Weak acid drugs are easily absorbed because of their low dissociation degree in the stomach. In the intestinal tract, weak basic drugs have a low dissociation degree and are the main absorption site of weakly basic drugs.
Strong acid and alkali drugs and ionic drugs are difficult to absorb. But once inside, it’s hard to get out.
In the same series of compounds, the smaller the molecular weight, the more easily absorbed.
The molecular weight of drugs that are effective orally is generally less than 500.
Surface area, residence time and pH affects drug absorption.
Oral cavity:fast-acting, directly into the circulation. Hypoglossal lozenges and oral collapse tablets. Small contact area, suitable for small doses of drugs.
Stomach:good blood circulation, long residence time, pH acid.Suitable for weak acid drug absorption.Gastric irritation.
Small intestine:moderate pH, large surface area, long residence time.First pass effect.
Large intestine:small surface area;Drug transformation can be carried out
Rectum:Blood flow is rich, directly into the blood, avoid gastrointestinal stimulation and liver metabolism.
Physicochemical properties and distribution of drugs:
Drug distribution refers to the drug through the capillary, leaving the blood circulation; Using blood flow to the site of action; Using concentration difference, by passive diffusion, into tissues and organs.
Capillaries are composed of lipid substances, and the pores on the wall of the tube are free to permeate water-soluble small molecules or ions.
Blood-brain barrier (BBB) :Specialized endothelial cells with no gaps. Drugs that cross the blood-brain barrier generally has high lipid solubility.
Lipophilicity:Distributed to tissues and must pass through cell membranes.
Appropriate fat-water partition coefficient.
Electric charge:It is difficult for charged molecules to pass through the cell membrane and the blood-brain barrier to bind to tissues or proteins, bind to plasma proteins, cannot pass through cell membranes or blood vessel walls, cannot diffuse into cells, and cannot be filtered by the glomerulus, which affects the volume of distribution and biotransformation. And excretion rate.
The binding with plasma protein can maintain a relatively stable blood drug concentration, so the adjustment of the inactive necessary structure in the drug molecule can change the balance of binding and dissociation, and prolong the action time of the drug.
Because this is a reversible non-specific binding, it does not directly affect the therapeutic effect but affects the pharmacokinetic process, thus indirectly affecting the effective concentration of the drug at the receptor site.
Can not be filtered by the glomerulus, affecting the volume of distribution, biotransformation, and excretion rate.
Drugs with strong lipophilicity have high affinity with tissue protein or adipose tissue, and strong binding: they have a long-term effect.
Hydrophobic groups such as alkyl groups, aromatic ring groups, and halogens increase the binding affinity to proteins.
Dissociable drugs can also bind to proteins through charge interactions.
The three-dimensional structure of the drug affects the binding of the drug to plasma proteins.
Different optical isomers of chiral drugs have different plasma protein binding effects.
Using the selective recognition and binding effect of certain tissues on specific ligands, the drug molecules are coupled with these ligands, and the drug molecules are selectively delivered to specific tissues to improve the selectivity of the drug action.
Active targeting: such as antibody-targeted drugs; receptor-targeted drugs
Passive targeting: Use the barrier function of the tissue to encapsulate the drug in liposomes or microspheres to prevent the drug from being distributed to the non-acting part, to avoid metabolic inactivation or toxic side effects.
The chemical change that occurs in the body of a drug is biotransformation, that is, metabolism.
In terms of physical and chemical properties, the result of the biotransformation of drugs is to increase polarity and water solubility to facilitate excretion, which is a protective mechanism of the body.
From the biological point of view, drug metabolites may lose activity, increase activity or produce toxicity; especially metabolite intermediates have strong chemical activity and may have strong toxic side effects.
The first step is to introduce (oxidize) or expose (reducing or hydrolyzing) polar groups in the molecular structure through oxidation, reduction or hydrolysis, such as -OH, -COOH, -SH, -NH2, etc.
Oxidation may form active products, such as cyclophosphamide, which plays an anti-cancer effect through oxidative metabolism to form active metabolites; it may also produce toxic and side effects.
The second step: the polar group is covalently combined with glucuronic acid, sulfuric acid, glycine, or glutathione to form a conjugate that is highly polar, easily soluble in water, and easily excreted from the body. This is the detoxification process.
The effect of drug metabolism on pharmaceutical properties The result of drug metabolism is the inactivation, activation, or new toxicity of the drug.
Due to individual differences in metabolic enzymes, individual differences in efficacy or toxicity will be caused, resulting in the unpredictability of pharmaceutical properties.
Because different drugs share the same metabolic enzyme, causing drug interactions.
Since metabolism is generally carried out in the liver, intermediates with higher chemical activity will be produced during the metabolic process, leading to liver toxicity.
The type and quantity of drug metabolizing enzymes will vary depending on age, species, heredity, gender, etc.
Drugs also induce or inhibit metabolic enzymes, resulting in drug resistance and drug interactions.
When drugs with the same metabolic mechanism are used in combination, the pharmacokinetic properties will change, resulting in drug interactions. Abnormal liver function can also affect the pharmacokinetic properties of the drug.
Glomerular filtration of free state of drugs and metabolites can be filtered by the glomerular; The filtration rate depends on the the concentration of the free drug and is not structure-specific.
Active secretion of renal tubules: Saturate about distributive coefficient.
Renal tubule reabsorption: The passage of uncharged drug molecules through the lipid membrane of renal tubule epithelial cells and back into the blood. Is a passive diffusion process. It is related to polarity, charge, dissociation, lipid solubility, etc.
It has polar groups and a larger molecular weight.
It is combined with glucuronic acid and excreted by bile.
The conjugate is hydrolyzed and absorbed by the small intestine into the enterohepatic circulation.
Affects the duration of the drug.
Pharmacokinetic properties of drugs with the same excretory pathway mechanism will also change when they are used in combination, resulting in drug interactions.
Abnormal renal function can cause drug accumulation, and toxic side effects.
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