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Talking about Pharmacokinetics PK

2021-10-14
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Pharmacokinetics (pharmacokinetics, PK) and pharmacodynamics (pharmacodynamics, PD), in fact, can be described as key research content, the two complement each other and are indispensable.
PK refers to the quantitative study of the changes in the in vivo processes such as absorption (A), distribution (Distribution, D), metabolism (Metabolism, M) and excretion (Excretion, E) of drugs in the body.

Absorb

Definition: The process by which a drug is transported into the blood from the site of administration

The administration site is usually divided into intravascular and extravascular administration. Intravascular administration generally refers to directly entering the blood through a vein or artery (without absorption process); extravascular administration includes oral administration, muscle, skin, etc. (into the blood must be absorbed Process), when the drug passes through the metabolic organs (such as the gastrointestinal wall and liver) for the first time when the drug is absorbed, the loss of the drug caused by the drug is called the first-past effect.

First pass effect

The evaluation index of drug absorption is bioavailability (BA), that is, the relative amount from the administration site to the blood circulation

For example, if 1g is administered and 0.5g of the drug enters the blood circulation, then let’s say that the BA of this drug is 50%. (This concept is very important, please remember, remember, remember!)

There are many factors that affect drug absorption, such as: route and location of administration (such as intravenous injection, intramuscular injection-remember the butt needle when you were a child? Oral-the most popular, safest, convenient, economical, and many advantages); physical and chemical properties of the drug (Such as acidity, alkalinity, solubility, etc.) and dosage form factors, physiological factors and pathological factors, etc.

For protein macromolecular drugs such as antibodies, the BA value after oral administration is extremely low, mainly because ① protein is easy to denature in acidic gastric juice; ② protein is easily degraded by a large number of hydrolytic enzymes in the gastrointestinal tract; ③ protein is large in size It has high polarity and is not easily absorbed by gastrointestinal epithelial cells through diffusion.

Therefore, most of the monoclonal antibody drugs are administered by intravenous injection (IV), and a small portion is administered by subcutaneous (SC) or intramuscular injection (IM). Antibodies injected subcutaneously or intramuscularly enter the body circulation mainly through the lymphatic circulation rather than the capillaries. System, the absorption is slow, and the peak time is delayed.

Distributed

Definition: The process by which the drug is distributed with the blood to various tissues of the body.

The way drugs pass through cell membranes

The rate and extent of its distribution are mainly related to tissue blood flow rate, physiological barriers (blood-brain barrier, placental barrier, etc.), drug and tissue affinity, drug plasma protein binding rate, drug fat solubility and other factors.

The index to measure whether the drug is widely distributed is the apparent volume of distribution (Vd), that is, when the drug absorption reaches equilibrium or steady state, the total amount of drug in the body (A) should theoretically be occupied according to the blood drug concentration (C) Volume volume, namely: Vd (L) = A (mg) / C (mg/L), the larger the value of Vd, it means that the drug is widely distributed in the body, on the contrary, it means that the distribution of the drug is limited and the tissue uptake rate is low.

For drugs, it is generally believed that the free form of the drug in the body is important for its efficacy. However, free macromolecular drugs may be the main source of immunogenicity, especially macromolecular drugs often do not bind to plasma proteins. The size of the molecular weight limits the biological products in the plasma (lymph) and interstitial spaces, but can bind to the target with a high affinity, which leads to an increase in the volume of distribution, and the interaction between biological products and their targets may affect Vd value.

Metabolism

The drug is often converted into a form that is easy to be excreted before excretion, such as decreased fat solubility and increased polarity, which is called drug metabolism. Drug metabolism is essentially an enzymatic reaction. For example, cytochrome P450 oxidase (CYP enzyme) plays an important role in drug-metabolizing enzymes in the liver. The activity of drug enzymes directly determines the time intensity of drug action.

Macromolecular drugs are usually not metabolized by CYP enzymes, and are mainly catabolized by proteolytic enzymes in the kidney (smaller molecular weight biological products) and liver. Its drug metabolism elimination pathways mainly include glomerular filtration, enzymatic hydrolysis, receptor-mediated endocytosis elimination and anti-drug antibody (AntiDrug Antibody, ADA)-mediated elimination.

Excretion

The process in which drugs absorbed into the body or metabolized products are discharged to the body. The main excretion pathways are excretion by the kidneys through urine, bile excretion, and fecal (intestinal) excretion.

Macromolecular drugs are mainly excreted through the kidneys. Due to the biological activity of macromolecular drugs themselves, their toxic effects are often related to drug effects. The main toxic effects are kidney toxicity and liver toxicity. At present, it is believed that the renal toxicity of macromolecular drugs is mainly due to the difficulty of renal excretion caused by large molecular weight, which is easy to cause inflammation [6]. On the other hand, certain antibody drugs may also trigger a cytokine storm and cause serious damage to the body.

Table 1 Comparison of ADMET(absorption,distribution,metabolism excretion and toxicity)characteristics between macromolecules and small molecules

Comparison of ADMET

Significance of Non-clinical Pharmacokinetics Assay

For more detail.

Regarding the significance of non-clinical pk research, I believe I don’t have to say more about it~

The most important thing, of course, is to provide an important basis for the design and optimization of clinical research dosing regimens, to ensure the safety and rationality of clinical research medications, and to help understand the target organs of drug efficacy or toxicity, and to clarify drug effects Or the material basis of toxicity, also provides important clues for pharmacodynamics and toxicology evaluation, and has guiding significance for the development of safer and more effective new drugs and the formulation of poisoning rescue measures.

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