ADME Properties

In the entire process of drug discovery, the optimization of the ADME (absorption, distribution, metabolism and excretion) properties of drug molecules is the most difficult part. The analysis of the properties of ADME plays a key role in the success of drug development.

Possible manifestations of poor properties of the candidate drug ADME

Increasing the dose did not increase the concentration of the drug in the serum-absorption problem

The concentration of the drug in the serum is appropriate, but the distribution in the brain is very small-Active efflux

Repeated administration but decreased serum concentration-induced enzyme activity

When taken together with other drugs, the blood concentration increases-inhibits enzyme activity

The time of action does not match the half-life-producing active metabolites or dissociating from the target too slowly

The overall strategy for ADME in the drug discovery process

At different stages of drug discovery, close attention to the molecular properties of drug candidates is indispensable.

Discovery of seed compound (Hit): Calculate the physical and chemical properties of the molecule, mark the ADME properties of the molecule; if possible, determine the logP/D and solubility experimentally.

The discovery of lead compounds: 96-well plates (or 384-well plates) to determine the cell permeability (PAMPA, MDCK-hMDR), microsomal stability, and inhibition rate of CYP3A (the most common CYP subtype in drug metabolism) , Pharmacokinetic determination in rats.

Optimization of lead compounds: 96-well plates (or 384-well plates) to determine the effect of compounds on transporters, the inhibition and induction of different subtypes of CYP, the binding of serum proteins, the stability of multi-species serum/microsomes/hepatocytes ( Human body, species used for research on pharmacodynamics, species used for research on safety); metabolite identification; determination of in vivo PK/PD relationship to explore drug efficacy; determination of in vivo PK to explore safety.

Discovery of candidate drugs (Candidate): Multi-dose safety study to predict human pharmacokinetics and drug-drug interactions. Conceive the formulation of a finished medicine, the maximum safe dose, the maximum tolerated dose.

PK/PD research

PK (pharmacokinetics, pharmacokinetics) is essentially the process of studying the change of drugs in the body over time, and the two-dimensional coordinate composed of time-drug concentration; PD (Pharmacodynamics, pharmacodynamics) is essentially the study of drugs in the body The process of changing the role of the drug over time, a two-dimensional indicator composed of time-pharmacodynamic indicators.

Both PK and PD are two independent in vivo parameter changes over time. In theory, it is not meaningful to split these two parameters: if you only look at the PK parameters, you can get the maximum plasma concentration, absorption in the body, metabolic rate and other parameters, but you cannot know the pharmacodynamic information; if you only look at PD Parameters can know the onset time and peak value of the drug, but cannot detect the real-time situation of the drug in the body. Under normal circumstances, the maximum value of PD lags behind the peak blood concentration of PK, so how much time does it lag? This answer is the simplest application in which PK/PD can be analyzed together to get the answer.

Therefore, in essence, PK/PD is a three-dimensional coordinate chart composed of drug concentration-pharmacodynamic index-time. Designing experiments to simultaneously measure the drug concentration and efficacy indicators in the body, and using relevant software on the market to build models is the basic process for studying the PK/PD relationship.

CYPs

CYP (cytochrome P450, cytochrome P450) is a large class of enzymes involved in drug metabolism, accounting for about 75% of the total number of various metabolic reactions. Most drugs are inactivated after being metabolized by CYPs and then excreted from the body; some substances are also metabolized by CYPs to produce their active form.

Many drugs can regulate the activity of CYPs by inducing the biosynthesis of a certain subtype (enzyme induction) or directly inhibiting the activity of CYP (enzyme inhibition). CYPs affect the metabolism and clearance of a variety of drugs is the main reason for most drug interactions. For example, if drug A inhibits the CYP of metabolizing drug B, the concentration of drug B in the body will continue to increase and eventually cause toxicity. Therefore, if you want to weaken or eliminate drug interactions, you need to adjust the dose of the drug or switch to another drug that does not react with the CYP system.

Further reading

books

1. Kwon Y. Handbook of essential pharmacokinetics,pharmacodynamics and drug metabolism for industrial scientists[M]. SpringerScience & Business Media, 2001.
2. Di L, Kerns E H. Drug-like properties: concepts,structure design and methods from ADME to toxicity optimization[M]. Academicpress, 2015.

FDA guidelines

Clinical DrugInteraction Studies – Study Design, Data Analysis, and Clinical Implications Guidance for Industry