What Is Pharmacokinetics?

Pharmacokinetic is a discipline that quantitatively studies the absorption, distribution, metabolism, and excretion of drugs in the body, and uses mathematical principles and methods to elaborate the laws of blood drug concentration over time.

Pharmacokinetic is a discipline that quantitatively studies the absorption, distribution, metabolism, and excretion of drugs in the body, and uses mathematical principles and methods to elaborate the laws of blood drug concentration over time.

Chinese name

Pharmacokinetics

Foreign name

Pharmacokinetic

Definition

Study the law of drug absorption and metabolism in the body

Including

Elimination kinetics

Pharmacokinetic properties

Pharmacokinetic requirements

Convenient administration: effective orally, once or twice a day (commonly used as anti-inflammatory analgesics, antihypertensive drugs, antibacterial drugs)

Targeted distribution or targeted activation: antitumor drugs

Fast onset: anti-allergic drugs, analgesics

Low drug interactions: conducive to combined use, such as the combination of lipid-lowering drugs and antihypertensive drugs

Long-term use does not produce drug resistance: such as antibacterial drugs, anticancer drugs, antiviral drugs.

No accumulation: If the drug or its metabolites cannot be excreted through an effective route, it will accumulate in the body and produce toxicity.

Pharmacokinetic importance

With the development of medicinal chemistry and the continuous improvement of human health, the requirements for the pharmacokinetic properties of drugs are becoming higher and higher: judging the application prospect of a drug, especially the market prospect, is not simply a strong curative effect and small toxic side effects; It must have good pharmacokinetic properties. Peptide drugs are the most typical example. In general, many biologically active peptides in the body, such as endorphins, have the characteristics of high efficiency and low toxicity, but they are unstable in the body and ineffective when taken orally.

Physico-chemical properties

Pharmacokinetic metabolic process

Absorption: After oral administration, the drug enters the digestive tract and is absorbed in different parts, such as the mouth, stomach, and intestines, and enters the blood.

Distribution: Drugs that enter the blood enter the site of action and produce a therapeutic effect or toxic side effects.

Metabolic transformation: Drugs undergo biological transformation in the liver or gastrointestinal tract through a series of redox reactions catalyzed by enzymes.

Excretion: Drugs or metabolites are excreted through the kidney (urine) or bile (feces) or by breathing.

For the convenience of expression, the internal process is often divided into three phases:

Medicinal phase: The tablet or capsule disintegrates and dissolves into a form that can be absorbed. (Pharmaceutical research content.)

Pharmacokinetics: Drug absorption, distribution, metabolism and excretion. (Pharmacokinetic research content.)

Pharmacodynamic phase: The interaction between the drug and the target, through stimulation and amplification, triggers a series of biochemical and biophysical changes, resulting in macroscopically observable activity or toxicity. (Pharmacological or toxicological research content.)

The three phases occur in sequence, but may coexist: for example, slow-release drugs, part of the drug has been distributed and exerts its pharmacological effect, but another part is still in the process of release and absorption. In particular, the pharmacokinetic and pharmacodynamic phases generally exist simultaneously.

Pharmacokinetic parameters

I. Absorption

Dissolution: the degree to which a drug molecule is dissolved in the digestive tract

Bioavailability: extent of drug absorption

Absolute bioavailability

Maximum blood concentration (Cmax)

Peak time (Tmax)

Second, the distribution

Due to the heterogeneity of the internal environment (blood, tissue), the rate of change in drug concentration varies.

Compartment (compartment): The rate of change of drug concentration in the same compartment is the same and homogeneous.

One-compartment model: The drug enters the bloodstream and distributes rapidly throughout the body and is continuously cleared.

Two-compartment model: After the drug enters the body, it is quickly distributed in the tissue and then enters a slower elimination process.

Apparent volume of distribution (Vd): Characterizes the ability of a drug to be taken up by tissues in the body. Drugs with a large apparent volume have a longer retention time.

Area under the drug concentration-time curve (AUC); Systemic Exposure

Blood-brain barrier; protein binding rate; distribution half-life (t 1/2 ()

Elimination

Elimination (elimination): the process of disappearing the original drug in the body. Includes renal (urine) or bile (faeces) or respiratory excretion and the sum of metabolic transformation.

Elimination constants: Reflects how quickly the drug disappears in the body. It 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 50% reduction in drug concentration or dose. Elimination of half-life t1 / 2 ()) Terminal Half-life, Elimination Half-life.

Clearance (clearance rate) or renal clearance (renal clearance): reflects the rate of excretion of drugs or metabolites through the kidneys.

Pharmacokinetic interaction

On the one hand, the effects of drugs on the body, which produce pharmacological effects, toxicity or side effects, are manifested in the pharmacological or toxicological effects of drugs, which are determined by specific chemical structures and have strong structural specificity.

On the other hand, the body's effects on drugs: absorption, distribution, biotransformation and excretion, manifested by the pharmacokinetic properties of drugs. It mainly depends on the physicochemical properties of the drug molecule, such as the solubility of the drug, the lipid-water partition coefficient, and the charge, and the structure specificity is not strong.

Pharmacokinetic absorption

Pharmacokinetic drug absorption

It is the process in which the drug enters the blood circulation through the biofilm from the administration site.

Pharmacokinetic absorption site

Digestive tract (oral administration, oral, 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, intramuscular injection; subcutaneous administration, oral.)

Common: Drugs are absorbed through biofilms.

Pharmacokinetic absorption process

Spread

Passive diffusion: the diffusion rate is proportional to the concentration gradient; no specificity; no saturation; the drug molecule must have a suitable lipid-water partition coefficient. Most chemicals are absorbed through passive diffusion pathways.

Membrane pore diffusion: Substances with a molecular weight of less than 100.

Facilitated diffusion: The participation of a transporter is required, which is saturated and specific; however, a certain concentration gradient is required. Such as cells take up glucose, methotrexate, and the small intestine absorbs VB12.

Transit

Active transport: The diffusion rate has nothing to do with the concentration gradient; it is structurally specific (nutrient molecules necessary for the body such as amino acids can be used as a carrier for drug transport), it is saturated; it does not need to have a certain lipid-water partition coefficient; it is an energy-consuming process.

Ion pair transport: Strongly dissociating compounds such as sulfonates or quaternary ammonium salts combine with endogenous substances to form charge-neutral ion pairs, which then pass through the lipid membrane in a passive diffusion pathway.

Puffing: fat, oil droplets, protein, etc. Cell receptor-mediated.

First pass effect: Drugs absorbed by the small intestine enter the liver through the portal vein and are metabolized in the liver

Enterohepatic circulation: Drugs in the liver are secreted with the bile into the gallbladder, and then discharged from the gallbladder to the small intestine, and finally absorbed in the small intestine through the portal vein and enter the liver.

Factors affecting pharmacokinetics

1.Water soluble

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 dissolved state before it can be absorbed. Therefore, the drug is required to have a certain water solubility.

Polarity (the introduction of polar groups can increase water solubility), crystalline form (the effect on the bioavailability of drugs is receiving more and more attention), and melting point all affect the solubility, thereby affecting drug absorption and affecting bioavailability.

2.Fat soluble

The structure of the double lipid layer of the cell membrane requires the drug to have a certain lipid solubility in order to penetrate the cell membrane. Come in (certainly fat soluble) and go out (certainly water soluble).

Easily dissociate groups such as carboxylates.

Through the modification of the chemical structure, the introduction of fat-soluble groups or side chains can improve the fat-solubility of the drug, promote the absorption of the drug, and increase the bioavailability.

3. Degree of dissociation

Drugs can only pass through biofilms in molecular form.

The biofilm itself has a charge, attracts each other, can get in, can't go out; phase repulsion: can't come in.

Ions have hydration, and the size of drug molecules increases, and they cannot pass through the pores of the biofilm.

Therefore, the larger the degree of dissociation, the worse the absorption.

The degree of dissociation is related to the dissociation constant of the drug and the pH of the absorption site. The same drug has different degrees of dissociation and absorption in different parts. Weak acid drugs have a low degree of dissociation in the stomach and are easily absorbed; in the intestine, weak alkaline drugs have a low dissociation degree and are the main absorption site of weak alkaline drugs.

Strong acid and alkali drugs and ionic drugs are difficult to absorb. But it is also difficult to come out after entering the cell.

4.Molecular weight

In the same series of compounds, the smaller the molecular weight, the easier it is absorbed.

The molecular weight of orally effective drugs is generally below 500.

Pharmacokinetic in vivo environmental effects

Surface area, drug residence time, and pH affect drug absorption.

Oral: quick onset, directly into circulation. Sublingual tablets, orally disintegrating tablets. Small contact area, suitable for small doses of drugs.

Stomach: Good blood circulation, long residence time, and acidic pH. Suitable for weakly acidic drugs. Stomach irritation.

Small intestine: moderate pH, large surface area, and long residence time. First pass effect.

Large intestine: small surface area; drug conversion possible

Rectum: rich blood flow, directly into the blood, to avoid gastrointestinal irritation and liver metabolism.

Physicochemical properties and distribution of drugs

Drug distribution means that the drug passes through the capillary and leaves the blood circulation; it reaches the site of action by the flow of blood; by virtue of the difference in concentration, it diffuses into the tissues and organs through passive diffusion.

Capillaries are composed of lipid substances, and the pores on the tube wall can freely permeate small molecules or ions that are water-soluble.

Blood-brain barrier: special endothelial cell composition without gaps. Drugs that cross the blood-brain barrier are generally more lipid-soluble.

Pharmacokinetic drug distribution

Lipophilicity: distributed to the tissue and must pass through the cell membrane.

Appropriate fat-water partition coefficient.

Charge: It is difficult for charged molecules to pass through the cell membrane and the blood-brain barrier to bind to tissues or proteins, to bind to plasma proteins, not to cross cell membranes or blood vessel walls, to diffuse into cells, or to be filtered by glomeruli, affecting distribution volume and biotransformation And excretion rate.

Pharmacokinetic plasma protein binding

Binding with plasma proteins can maintain a relatively stable blood drug concentration, so adjusting the inactive must-have structure in the drug molecule can change the balance of binding and dissociation and prolong the drug's action time.

Since this is a non-specific binding reversible binding, it does not directly affect the efficacy, but affects the pharmacological process, and thus indirectly affects the effective concentration of the drug at the receptor site.

Can not be filtered by the glomerulus, affecting distribution volume, biotransformation and excretion rate.

Factors affecting pharmacokinetics

Drugs with strong lipophilicity have high affinity with tissue proteins or adipose tissue, and have strong binding: they have a long-lasting effect.

Hydrophobic groups such as alkyl, aromatic ring, and halogen increase the binding affinity to proteins.

Dissociable drugs can also bind to proteins through charge interactions.

The three-dimensional structure of a drug affects its binding to plasma proteins.

Different optical isomers of chiral drugs have different plasma protein binding effects.

Pharmacokinetic specific distribution

By utilizing the selective recognition and binding effect of certain tissues on specific ligands, drug molecules are coupled to these ligands, and drug molecules are selectively delivered to specific tissues to improve the selectivity of drug effects.

Targeted pharmacokinetics

Active targeting: eg antibody-directed drugs; receptor-targeted drugs

Passive targeting: The barrier effect of the tissue is used to encapsulate the drug in liposomes or microspheres to prevent the drug from being distributed to non-active sites, so as to avoid metabolic inactivation or toxic side effects.

Pharmacokinetic drug metabolism

The chemical change of a drug in the body is biological transformation, that is, metabolism.

From the perspective of physicochemical properties, the result of drug biotransformation is to increase its polarity and water solubility to facilitate excretion, which is a protective mechanism for the body.

From a biological point of view, the metabolites of a drug may lose activity, may also increase activity or produce toxicity; especially metabolic intermediates, which have strong chemical activity, may have strong toxic and side effects.

Pharmacokinetic biotransformation

In the first step, polar groups such as -OH, -COOH, -SH, -NH2 are introduced (oxidized) or exposed (reduced or hydrolyzed) into the molecular structure through oxidation, reduction or hydrolysis.

Oxidation may form active products such as cyclophosphamide, which exerts anti-cancer effects through oxidative metabolism to form active metabolites; it may also produce toxic side effects.

The second step: the polar group is covalently bonded to glucuronic acid, sulfuric acid, glycine or glutathione to form a conjugate with high polarity, 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 drugs.

Factors affecting pharmacokinetics

Due to individual differences in metabolic enzymes, it may cause individual differences in drug efficacy or toxicity, resulting in unpredictable pharmaceutical properties

Because different drugs share the same metabolic enzyme, causing drug interactions

Because metabolism is generally carried out in the liver, intermediates with high chemical activity are produced during metabolism, which causes liver toxicity.

Depending on age, species, genetics, gender, etc., the types and quantities of drug metabolizing enzymes will vary.

Drugs can also induce or inhibit metabolic enzymes, resulting in drug resistance and drug interactions.

For drugs with the same metabolic mechanism, the pharmacokinetic properties will change when the drugs are combined, resulting in drug interactions. Abnormal liver function can also affect the pharmacokinetic properties of the drug.

Pharmacokinetic drug excretion

Pharmacokinetic renal excretion

The glomerular filtration drug and metabolites in the free state can be filtered by the glomerulus; the filtration rate depends on the concentration of the free drug and has no structure specificity.

Active secretion of renal tubules: It is related to the partition coefficient and is saturated.

Renal tubular reabsorption: Uncharged drug molecules cross the lipid membrane of renal tubular epithelial cells and return to the bloodstream. It is a passive diffusion process. Related to polarity, charge, dissociation degree, fat solubility, etc.

Pharmacokinetic bile exclusion

It has a polar group and a large molecular weight.

Combined with glucuronic acid, etc., excreted by bile.

The conjugate is hydrolyzed, absorbed by the small intestine, and enters the enterohepatic circulation.

Affects the duration of the drug.

For drugs with the same excretion pathway mechanism, the pharmacokinetic properties will also change when the drugs are combined, resulting in drug interactions.

Abnormal renal function can cause drug accumulation and produce toxic and side effects.

Pharmacokinetic New Drug Design

Optimizing pharmacokinetic properties is one of the important contents of drug design. Through structural modification or molecular design to optimize the absorption and distribution of drugs, it can break through foreign patent protection drugs. In general, the optimization of pharmacokinetic properties does not involve the basic structure of the drug. Therefore, the probability of success is high, and it is possible to obtain drugs with independent intellectual property rights at the lowest cost. According to the results of metabolic studies, structural optimization is performed to achieve predictability or controllability of pharmacokinetic properties and reduce individual differences and drug interactions.

Pharmacokinetic leader or drug

Metabolites act faster as drugs (in their active form), have stronger effects or fewer side effects, and have less drug interactions (no further metabolism is required). For example, from terfenadine to fexonadine, loratadine to Desloratadine, astemizole to norastemizole, cisapride to nordesamin.

Pharmacokinetic prodrug or soft drug

Increase bioavailability

Targeted release: The difference in enzymes or pH specific to the target tissue or target organ is used to achieve localized hydrolysis of the prodrug to improve the selectivity of the action.

Enzyme-prodrug therapy in antitumor drug research: the enzyme (not in the body) is selectively delivered (antibody-targeted or receptor-targeted) or expressed (gene-targeted) in the target tissue, the prodrug is hydrolyzed, and the cytotoxicity is released Drug molecule.

Improve bioavailability

Designing soft drugs to achieve controlled metabolism, such as the design of the hypoglycemic drugs reglinide and nateglinide, which have fast onset and short effect time, can effectively control the increase of postprandial blood glucose, while avoiding low blood sugar and obesity The side effects of regulating blood glucose levels more physiologically are called drugs that think like islets.

Pharmacokinetics Prolong Action

According to the results of pharmacokinetic studies, the site of drug metabolism is blocked and the adverse drug metabolism is blocked. Such as fluorine substitution on the benzene ring to block the unfavorable metabolism on the benzene ring. Metabolic groups such as hydroxyl groups are introduced in advance to improve drug activity or accelerate the onset time.

Computer aided pharmacokinetics

Pharmacokinetic screening

The evaluation of preclinical pharmacokinetics has been involved earlier and earlier in the process of drug development research:

In vitro pharmacodynamics-in vivo pharmacodynamics-safety-pharmacokinetics

In vitro pharmacodynamics-pharmacokinetics-in vivo pharmacodynamics-safety

Similar to the development of high-throughput pharmacodynamic screening technology, high-throughput pharmacokinetic screening methods are also being established and applied. Similarly, in order to improve the scientificity of drug design, computer-assisted virtual screening technology has been developed, models have been established and optimized, and virtual screening has been performed through models, such as the discovery of the new lipid-lowering drug Enzetimbe. Virtual screening technology for pharmacokinetics has also been valued by medicinal chemists.