Popular science essay: Fat-water partition coefficient and drug activity are "connected"

The drug needs a certain degree of hydrophilicity, and it also needs to have a certain degree of lipophilicity, that is, amphiphilicity is conducive to absorption
.
Drugs with too high or too low hydrophilicity or lipophilicity have adverse effects on drug efficacy
.
This property is commonly expressed by the fat-water partition coefficient, also known as the oil-water partition coefficient.
The larger the value, the more soluble in fat, and vice versa
.
In this paper, the definition of lipid-water partition coefficient, the method of calculating lipid-water partition coefficient, the influencing factors of lipid-water partition coefficient, the influence of lipid-water partition coefficient on drug development, and the summary will share the relationship between lipid-water partition coefficient and drug activity.
Connected"
.
Definition of the fat-water partition coefficient The fat-water partition coefficient of an organic compound usually refers to the partition coefficient of the compound between n-octanol and water, which is expressed by its logarithm and recorded as logP: where Coct and Cw are the compounds in n-octanol and water, respectively.
The concentration at which equilibrium is reached between the two phases of water
.
Usually P gives the partition coefficient of the neutral compound between the two phases
.
For ionizable compounds, the partition ratio D is used to represent the total partition coefficient of the solute between the two phases
.
For example, for the ionizable solute HA may have: where [HA], [A-] represent the concentrations of the neutral and ionic states of the solute, respectively
.
D is a parameter related to the acid-base dissociation constant pKa of the solute and the pH of the solution
.
Therefore, the pH value is often used as a suffix when denoting LogD, such as LogDpH7.
4
.
Methods for calculating the partition coefficient of lipids and water Commonly used methods for the determination of compound logP include shake flask method, reversed-phase high performance liquid chromatography and software prediction
.
Therefore logP can be obtained by experiments or software prediction methods
.
However, the experimental method needs to obtain substances with higher purity, and it takes a long time and costs a lot. .
Although the data obtained by the software prediction method is slightly less accurate, it has many advantages such as fast speed, no need to obtain materials, and low cost, and is welcomed by many researchers
.
1 Shaking flask method In simple terms, the shaking flask method is to shake a flask containing two immiscible solvents and one solute.
After reaching equilibrium, analyze the concentration of the solute in one or two phases, thereby calculating logP
.
In 2013, Tianjin Institute of Materia Medica Mi Nan et al.
[1] used n-octanol-phosphate buffer as the dispersion system and the shake flask method as the measurement method, and used UV-Vis spectrophotometry for the determination
.
The oil-water partition coefficient was calculated by the concentration ratio of azilsartan in the oil phase (n-octanol) and the water phase after partition equilibrium
.
In the n-octanol-phosphate buffer system, the oil-water partition coefficient of Azilsartan was 3.
78 when pH=3.
0, and the oil-water partition coefficient of Azilsartan was -0.
30 when pH=7.
0
.
2 Reversed-phase high-performance liquid chromatography Reversed-phase high-performance liquid chromatography is widely used for indirect determination of compound or drug logP
.
This approach is based on a model that correlates the retention properties of compounds with the distribution system
.
The logP of the compound can then be calculated from the retention properties of the compound in the separation system
.
Table 1.
HPLC analysis results of 21 standard compounds[3] Reversed-phase high performance liquid chromatography has the advantages of simple operation, rapidity, low cost and good repeatability.
It is a good indirect determination method, but this method Selecting different standard compounds has a great influence on the experimental results [2]
.
Song Bin et al.
[3] determined the n-octanol/water partition coefficient (Kow) of several phenolic compounds by reversed-phase high performance liquid chromatography, established the relationship equation between the capacity factor (k) and Kow, and investigated the standard.
The influence of the structure of the sample compound on the determination results
.
As shown in Table 1, the experimental results show that reversed-phase high performance liquid chromatography is an effective method for the determination of Kow, and the structure of the standard compound has a great influence on the determination results
.
3 There are many software and websites for software prediction software prediction, such as 10 commonly used partition coefficient (n-octanol/water) prediction software (ALOGPs, AC logP, AB/LogP, COSMOFraq, miLogP, ALOGP, MLOGP, KOWWIN, XLOGP 2, XLOGP 3) [4,5]
.
But chemists often use ChemBioDraw Ultra for preliminary clogP predictions [6,7], as shown in Figure 1 for azilsartan logP predictions
.
This is because chemists basically install ChemBioDraw Ultra (a professional and reliable tool for drawing chemical molecular structures and chemical graphics), which is more convenient to use
.
Figure 1.
Using ChemBioDrawUltra to predict the logP of Azilsartan.
Factors affecting the lipid-water partition coefficient.
Changes in the molecular structure of the drug.
When the ability of the functional groups in the molecule to form hydrogen bonds and the degree of ionization of the functional groups are greater, the water solubility of the drug will increase
.
Such as amino, hydroxyl, nitro, sulfonic acid and so on
.
On the contrary, if the drug structure contains large non-polar structures such as hydrocarbon groups, halogen atoms, alicyclic rings, etc.
, the lipid solubility of the drug increases
.
Sufficient hydrophilicity can ensure that the drug molecules are dissolved in the water phase, and suitable lipophilicity can ensure the permeability of the drug to the cell membrane
.
Therefore, the effect of functional groups on the lipid-water partition coefficient should be fully considered when designing drugs in medicinal chemistry [8]
.
The influence of lipid-water partition coefficient on drug development As shown in the flow chart, different drugs have different requirements for lipid-water partition coefficient
.
As shown in Table 2, drugs acting on the central nervous system need to pass through the blood-brain barrier, so a larger lipid-water partition coefficient is required
.
Acting on the local area, it does not need to penetrate the blood-brain barrier to enter the brain tissue.
The requirements for lipid solubility are different from those of general anesthesia.
However, when penetrating the local nerve tissue cell membrane, it must have a certain degree of lipid solubility to penetrate the lipid biomembrane.
Local concentration is high
.
Table 2.
LogD value and its impact on drug development[9] Summary of lipid-water partition coefficient For medicinal chemistry research, the lipid-water partition coefficient is an important physical and chemical property
.
They are used to study the behavior of organic compounds in living organisms and are important parameters in many biological and physicochemical processes
.
Only when drugs can be freely transported in the body and smoothly pass through the biofilm until they reach the lesions, can they play a role in treating diseases
.
Therefore, some basic properties of organic compounds, such as pharmacokinetic properties such as absorption, distribution, metabolism, and excretion, as well as toxicity, are very important to whether they can finally be turned into medicines
.
About 70% of the human body is composed of water, and the content of water in plasma is as high as 90%
.
This indicates that the transport process of the drug in the human body is closely related to the water solubility of the drug
.
The lipid bilayer of biological membranes is hydrophobic, so the process of drugs passing through various biological membranes can be regarded as redistribution between water and hydrophobic media, so this process is closely related to its lipid-water partition coefficient [8]
.
If the water solubility of an organic compound is poor, which affects its absorption process in the body, its drugability is generally poor
.
Lower solubility may also have a large impact on the mode of administration
.
In general, the prediction of lipid-water partition coefficient and solubility data in the early stage of drug development has a great impact on whether the compound can be finally formulated as a drug. .
References [1] Mi Nan, Su Mujun, Zang Kexin.
Determination of the oil-water partition coefficient of Azilsartan [J].
Drug Evaluation Research, 2013, 36(06): 452-454.
[2] Liang Chao, Qiao Junqin, Han Yiyuan, et al.
Determination of n-octanol/water partition coefficient by cholesterol-based bonded phase-reversed-phase high performance liquid chromatography [J].
Chromatography, 2016, 34(12):1240-1248.
[3] Song Bin, Zhang Hongzhe.
Reversed-phase Determination of n-octanol/water partition coefficient of phenolic compounds by high performance liquid chromatography [J].
Shandong Chemical Industry, 2011, 40(03): 67-71.
[4] Shang Zhaocong, He Shaopeng.
Comparative study on prediction software of n-octanol/water)[J].
Science and Technology Herald, 2012, 30(19):63-69.
[5]STéENE JL, NYBERG N, LEHEL S, et al.
Development of a simple proton nuclearmagnetic resonance -based procedure to estimate the approximate distributioncoefficient at physiological pH (logD7.
4): evaluation and comparison toexisting practices[J].
Bioorganic & Medicinal Chemistry Letters, 2017,27(2):319-322.
[6]SAKAIT, NODA N , FUJIMOTO C, et al.
Ion-Pair Extraction of Quaternary Ammoniums Using Tetracyanocyclopentadienides and Synthetic Application for ComplexAmmoniums[J].
Org Lett, 2019, 21(9):3081-3085.
[7]VRAKAC,