Analysis of the role of pharmacokinetic parameters in candidate compound identification

 A large number of candidate compounds is the basis for drug development, and compound activity screening and testing are critical to obtaining candidate compounds with clinical safety data. In screening candidate compounds, pharmacokinetic parameters are another important screening metric to examine potential compounds in addition to their efficacy, which can be used to better control drug development time and reduce drug development costs by excluding candidates with suboptimal pharmacokinetic parameters early in drug development.

Image from pixabay

Modern advances in science and technology have greatly accelerated the rate of drug candidate discovery, with thousands of new compounds requiring screening each year. When a candidate compound enters the clinical phase, it is usually studied in healthy volunteers to obtain the kinetic parameters of the drug in humans. 

A large number of candidate compounds are often eliminated for pharmacokinetic reasons. Important pharmacokinetic parameters such as volume of distribution, clearance, half-life, and bioavailability determine the extent and duration of drug exposure in vivo. Early prediction of these parameters in vivo during the development of new drugs is of great importance for selecting and optimizing potential candidates.

Some investigators have used drug transporter evaluation methods, mainly using cultured cells expressing human drug transporter genes, where the host cell surface expression protein is also functionally very similar to the human transporter protein in vivo and thus can be used to provide pharmacokinetic data approximating clinical trials in the early stages of drug development, to rapidly screen out candidate compounds that do not have pharmacokinetic parameters, and thus to The goal is to shorten the development cycle and minimize unnecessary development costs.

Pharmacokinetic studies are needed better to understand the changes in drugs in the body, to design and optimize drug delivery, to guide rational drug use, and to provide a scientific basis for clinical drug use. Medicilon Pharmacokinetics Lab has passed the GLP certification by NMPA/ NMPA.Following the guiding principles of ICH, NMPA and FDA. The lab offers in vivo and in vitro pharmacokinetic tests according to our client's needs and provides them with complete sets of pharmacokinetic evaluation and optimization services.

There are many studies to identify candidate compounds by studying their pharmacokinetic parameters. For example, one researcher used a molecular docking virtual screening method to construct a natural product library containing 42,296 small molecules, which were docked to the protein tyrosine phosphatase 1B (PTP1B) target for the treatment of type II diabetes. The molecular docking[1]was performed, the binding energy of the original ligand was used as the threshold value, and the small molecules with scoring values higher than the threshold value were selected for the prediction of pharmacokinetic and toxicity parameters after three rounds of screening. Therapeutic agents.

Some researchers have also used high-performance liquid chromatography to determine the concentrations of anthraquinones (aloe-emodin, emodin, rhein, Chrysophanol, and physcion ) in tissues and plasma[2]. After gavage administration of different preparations, the pharmacokinetic parameters and distribution characteristics of rhubarb anthraquinones were studied in rabbits and rats. The results showed that their elimination processes in rabbits and rats satisfied the two-compartment model. 

There were no statistical differences in the main pharmacokinetic parameters calculated by the amount of rhubarb acid and total anthraquinone for the processes in rats. Rhubarb anthraquinones were mainly distributed in the kidney, liver, heart, and blood and decreased sequentially. Anthraquinones were present in the body mainly as rhubarb acids and excreted by the kidneys. The pharmacokinetic study of compound preparations containing rhubarb analogs in vivo can be carried out using rhubarb acid as an indicator component.

In the study of active compounds, the final determination of whether they can become drugs with therapeutic effects is inseparable from their pharmacokinetic properties and the safety of the drugs. In conclusion, pharmacokinetics plays a crucial role in the drug development process and is indispensable throughout the entire process of drug discovery and preclinical and clinical research.

[1] Virtual screening of natural product-based protein tyrosine phosphatase 1B inhibitors[J].

[2] Distribution and pharmacokinetics of five rhubarb anthraquinones in rabbits and rats[J].