Study on pharmacokinetics and tissue distribution of hydroxybenzoic acid and its sodium salt in mice and crab eating macaques
P-hydroxybenzoic acid (p-HBA) is a monophenolic acid commonly found in nature, found in higher plants, microorganisms, mosses, and soil. It has various pharmacological activities such as antibacterial, antioxidant, anti-inflammatory, and anticancer properties. Previous studies have found that p-HBA is the active metabolite of hydroxybenzaldehyde, an active ingredient in ground vegetables, which exerts anti colitis effects by inhibiting inflammatory reactions and improving intestinal mucosal damage. It can be seen that p-HBA can serve as a potential compound for the treatment of ulcerative colitis and has good development prospects. However, the preliminary research results of the research group showed that p-HBA has poor water solubility and is accompanied by adverse reactions such as splenomegaly, which seriously affects its further development. Therefore, the research team conducted a study on its sodium salt, sodium p-hydroxybenzoate (s-HBA), and found that it has good stability, no obvious side effects, and good water solubility. Its pH is close to neutral or weakly acidic, making it convenient for medical use without changing its pharmacological activity; From the perspective of drug metabolism, salted drugs are more easily absorbed and utilized by the human body. At the same time, in order to further understand the absorption and distribution patterns of p-HBA and s-HBA in vivo, this paper conducted a systematic study on the pharmacokinetics and tissue distribution characteristics of pHBA and s-HBA, providing scientific basis for the further development and utilization of s-HBA.

 

This study is based on previous pharmacological experiments, and in the later stage, pharmacokinetic studies will continue on mice with ulcerative colitis to investigate the effects of their pathological status on the pharmacokinetics of p-HBA and s-HBA. In order to maintain consistency with pharmacological studies, C57BL/6 mice, which are most similar to human colitis in terms of histopathology, will continue to be used for pharmacokinetic experiments. In the preliminary experiment, this study designed dense sampling points with a sampling duration of 24 hours. Based on the results of the preliminary experiment, experimental designs were carried out on the absorption phase, distribution phase, and elimination phase of p-HBA and s-HBA. The formal experimental sampling duration was 4 hours, with a total of 8 sampling points. Based on pharmacological and safety experiments, the final dose of p-HBA was determined to be 20mg/kg, and the dose of sHBA after salt coefficient correction was 20, 50, and 100mg/kg. In pharmacokinetic studies, two drugs were administered at the same dose of 20mg/kg; In the study of organizational distribution, both drugs were selected for the optimal dose. As the optimal dose for p-HBA was 20mg/kg and the optimal dose for s-HBA was 100mg/kg, p-HBA (20mg/kg) and sHBA (100mg/kg) with a 5-fold difference in dose were chosen for single administration to investigate their tissue distribution. In addition, pharmacokinetic experiments of s-HBA in crab eating macaques were designed. After equivalent dose conversion, the final dosages were determined to be 4, 10, and 20mg/kg, with a sampling time of 6 hours and a total of 13 time points.
The degree of absorption of drugs in the body directly affects their effectiveness, and the speed of elimination is closely related to their duration of action. From the pharmacokinetic experiments in mice, both p-HBA and s-HBA showed good pharmacokinetic processes after oral administration, with rapid absorption and elimination in plasma, and no obvious accumulation in vivo. At the same dose, the Cmax and AUC of s-HBA were slightly higher than those of p-HBA, while V and Cl were slightly lower, but the difference was not statistically significant. This may be due to the poor water solubility of pHBA, which, when derived into sodium salts, greatly increases the water solubility of s-HBA. After oral administration, it may be more evenly distributed in various layers of gastric mucus and absorbed more fully. S-HBA also exhibits good pharmacokinetic processes in crab eating macaques, and is rapidly absorbed and eliminated; Under three doses of oral administration, the Cmax and AUC0-t of s-HBA in mice and crab eating monkeys showed a good linear relationship with the dose. In addition, the MRT0-t, V, and Cl of s-HBA in mice were slightly lower than those in crab eating monkeys, with a difference of 2-3 times, and the difference was not too significant. Overall, the process of s-HBA in rodents and non rodents is relatively stable, with no specific absorption or elimination.
After entering the body, drugs will be transported to various tissues through the circulatory system. Due to the differences in drug distribution in the body, it can affect the therapeutic effect, accumulation, and toxic side effects of drugs. Therefore, studying the distribution of drugs in various tissues is of great significance for drug development and improvement. The organizational distribution results showed that after administration of p-HBA and s-HBA, both rapidly distributed and eliminated in the tissue, with peak times concentrated between 0.03-0.17 hours and elimination exceeding 80% after 1 hour. PHBA is widely distributed in tissues, with the highest concentration in the kidneys and liver, followed by the lungs, heart, and spleen. These tissues are all tissues with abundant blood flow and small capillary barriers, which may be one of the reasons for the high concentration distribution. In addition, it is speculated that p-HBA may be mainly excreted by the kidneys and metabolized by the liver in the body; It may also be the main site of drug accumulation, which is consistent with the mild renal and hepatic toxicity observed in previous studies at the maximum tolerated dose of s-HBA. A certain concentration of p-HBA was detected in brain tissue, indicating that it can pass through the blood-brain barrier. A rather special situation is that there is a significant difference in the concentration of p-HBA in the colon after administration of p-HBA and s-HBA. The tissue distribution size after p-HBA administration is kidney>liver>lung>colon>heart>spleen>brain, while after s-HBA administration, it is kidney>liver>lung>heart>spleen>colon>brain. The reason is not yet clear, which may be related to p-HBA and s-HBA as potential drugs for treating colitis, while the colon is the main organ involved in colitis lesions. Subsequent experiments will further verify this.
In summary, both p-HBA and s-HBA have good pharmacokinetic processes, with rapid absorption and elimination in vivo. They are widely distributed in tissues, with the highest concentration in the kidneys and liver, indicating tissue targeting and the ability to pass the blood-brain barrier. These all demonstrate the promising development prospects of p-HBA and s-HBA. There are studies indicating that pathological conditions have an impact on multiple drug processes. The research team will now explore whether the pharmacokinetics and tissue distribution of p-HBA and s-HBA change under pathological conditions, providing more references for subsequent studies.