Pharmacokinetic is a discipline that quantitatively studies the absorption, distribution, metabolism and excretion of drugs in organisms, and uses mathematical principles and methods to overcome the law of changes in blood drug concentration over time.
Physical and chemical properties
Absorption: After oral administration, the drug enters the digestive tract, is absorbed in different parts such as the mouth, stomach, and intestines, and enters the bloodstream.
Distribution: The drug entering the blood enters the site of action, producing therapeutic effects or side effects.
Metabolic transformation: Drugs undergo biotransformation in the liver or gastrointestinal tract through a variety of enzyme-catalyzed redox reactions.
Excretion: Drugs or metabolites are excreted via the kidney (urine) or bile (feces) or breathing.
For the convenience of presentation, the processes in the body are often divided into three phases:
Pharmacist phase: The tablet or capsule disintegrates, dissolves, and becomes an absorbable form. (The pharmacist studies the content.)
Pharmacokinetic phase: drug absorption, distribution, metabolism and excretion. (Content of pharmacokinetic research.)
Pharmacodynamic phase: the drug interacts with the target, through stimulation and amplification, it triggers the biochemical and biophysical changes of the interaction, resulting in the macroscopic observation of its activity or toxicity. (The content of pharmacology or toxicology research.)
The three times occur one after another, but may exist at the same time: such as sustained-release drugs, some drugs have completed their distribution and exert pharmacological effects, but the other part is still in the process of release and absorption. In particular, the pharmacokinetic phase and the pharmacodynamic phase generally exist simultaneously.
1.Absorb
Dissolution: the degree to which the drug molecule is dissolved in the digestive tract
Bioavailability: the degree of drug absorption
Absolute bioavailability
Maximum blood concentration (Cmax)
Peak time (Tmax)
2. Distribution
Due to the inhomogeneity of the internal environment (blood, tissue), the rate of drug concentration changes is different.
Compartment (compartment): The drug concentration in the same compartment changes at the same speed and is homogeneous.
One-compartment model: The drug enters the blood and is rapidly distributed throughout the body, and is continuously removed.
Two-compartment model: After the drug enters the body, it first quickly distributes in the tissue, and then enters a slower elimination process.
Apparent volume of distribution (Vd) (apparent volume of distribution): indicates the ability of the drug to be transported by tissues in the body.
Area under the drug concentration-time curve (AUC); systemic drug exposure (systemic exposure)
Blood brain barrier; protein binding rate; distribution half-life (t 1/2 (α)
3. Eliminate
Elimination (elimination): The process by which the original drug disappears in the body. Including the sum of kidney (urine) or bile (feces) or respiratory excretion and metabolic transformation.
Elimination rate constant (elimination constant): Reflects how fast the drug disappears in the body. Does not fully reflect the duration of action of the drug (metabolites are also active).
Half-life or half-life (t1 / 2): The time required for a drug concentration or dose to decrease by 50%. Elimination half-life t1 / 2 (β)) terminal half-life, elimination half-life.
Clearance (clearance, contour clarity) or renal clearance (renalclearance): Reflects the speed at which drugs or metabolites are excreted from the body through the kidneys.
Water solubility
Water is the carrier of drug delivery, and the medium in the body is water. The drug must have a certain degree of water solubility at the absorption site and be in a dissolved state before it can be absorbed. Therefore, a certain supplement of drugs is required.
Polarity (dating polar groups can increase the increment), crystal form (the effect on drug bioavailability is receiving more and more attention), melting point all affect solubility, thereby affecting drug absorption and bioavailability.
Fat-soluble
The structure of the double lipid layer of the cell membrane requires the drug to have a certain degree of fat solubility to penetrate the cell membrane. Can come in (a certain degree of fat solubility), can go out (a certain degree of selectivity).
Esterify easily dissociable groups such as doping.
By modifying the chemical structure, introducing fat-soluble groups or side chains can improve the fat-soluble properties of the drug, promote the absorption of the drug, and improve the bioavailability.
Dissociation degree
Drugs can only pass through biological membranes in molecular form.
The biofilm itself is toxic, attracts each other, can come in, cannot get out; repel: cannot get in.
Ions have hydration, and the volume of drug molecules expands and cannot pass through the micropores of biological membranes.
Therefore, the dissociation degree value, the worse the absorption.
The same drug has different dissociation degrees in different parts and different absorption degrees. The degree of dissociation of weakly acidic drugs in the stomach is small and is easy to be absorbed; in the body, the degree of dissociation of weakly basic drugs is small, and it is the main absorption site for weakly basic drugs.
Strong acid and strong base drugs and ionic drugs are difficult to absorb. But it is difficult to get out after entering the cell.
Molecular weight
In the same series of compounds, the smaller the molecular weight, the easier it is to be absorbed.
The molecular weight of oral effective drugs is generally below 500.
It is the main organ for drug excretion. The original drug excreted through the vein can be reabsorbed in the renal tubules, prolonging the action time of the drug. The degree of reabsorption is affected by the pH of the urine. The application of acidic or alkaline drugs to change the pH of the urine can reduce the reabsorption of the drug by the renal tubules.
Some drugs, such as digitalis toxic compounds, are partially excreted into the small intestine with bile after binding to glucuronic acid in liver cells. After the small intestine is replaced, free drugs are absorbed again, which is called hepatoenteric circulation (hepatoenteric circulation). , Can be taken to cancel cholamine, cholestyramine can be combined with digitalis toxin, the conjugate is excreted with feces, interrupting the hepato-intestinal circulation. The pH of breast milk is slightly lower than that of plasma, and the basic drug part can be excreted from breast milk. Drugs that are excessively excreted from milk should be aware of their effects on infants.
Medicilon can provide you with pharmacokinetic (PK) experiments of different species of animals such as mice, rats, rabbits, etc. through SPF animal laboratory, and the methods and methods are intravenous, intragastric, subcutaneous, and abdominal cavity.
Identification of metabolites
Pharmacy/toxicity sample analysis (ELISA, LC-MS, MS), etc.
Medicilon Preclinical Research-Early Pharmacokinetics (Discovery DMPK) Team
Pharmacokinetic test / toxicokinetic test
Pharmacokinetic Analysis Service
Preclinical Pharmacokinetic Study Service
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