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DMPK and Mechanism of Drug Interaction

2021-09-14
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When treating diseases, patients often need to receive more than one drug to enhance the therapeutic effect. When multiple drugs are administered at the same time, drug-drug interaction (DDI) may occur. Drug interaction based on pharmacokinetics is one of the main ways of drug interaction, including the interaction in the four links of drug absorption, distribution, metabolism, and excretion. The consequence is that it can change the blood drug concentration. At present, many drugs have been withdrawn from the market due to drug interactions in the metabolic link, causing serious adverse reactions. Therefore, the study of metabolic drug interactions is very important.

Drug interactions are very common. Some patients get worse after taking the medicine, and some people have adverse reactions after taking some medicines, which may be caused by the interaction between the medicines. In the final analysis, drug interactions have two results: enhanced effects and weakened effects. From a clinical point of view, enhanced effects can be manifested as improved curative effects or increased toxicity; and weakened effects can be manifested as reduced toxicity or reduced curative effects. Due to drug safety considerations, toxicity caused by drug interactions has attracted much attention.

Drug interaction may reflect the pharmacokinetic process, pharmacodynamic process, or both, and the interaction mechanism of some drugs is still unclear. Medicilon’s pharmacokinetic laboratory has passed CFDA’s GLP certification. The experimental research follows the guidelines of ICH, CFDA and FDA. It can design and carry out in vivo and in vitro pharmacokinetic tests according to customer needs, and provide customers with a complete set of pharmacokinetics. Dynamic evaluation and optimization services.

The four processes that determine the pharmacokinetics of drugs may be affected by drugs, including absorption, distribution, metabolism and excretion. When a drug enters the body, it mainly affects the metabolism of the drug in three ways:

(1) Cytochrome enzyme glucuronidation, the drug may induce or inhibit CYP and affect the metabolism of the drug;

(2) Transporters, drugs may affect transporters, OATP or P-gp, etc., and affect the distribution and metabolism of drugs;

(3) Protein binding, drugs may compete for plasma protein binding and affect the distribution of drugs.

In the case of psychiatric drugs, interactions involving psychiatric drugs are not uncommon, and can often lead to changes in blood drug levels or drug efficacy. Fortunately, most psychiatric drug interactions are not seriously harmful; however, some drug interactions still have potentially catastrophic harm, such as 5-HT syndrome, fatal arrhythmia related to prolonged QT interval, etc. . Taking psychiatric drugs as an example, the mechanism of drug interactions is introduced from the perspectives of absorption, distribution, metabolism, and excretion.

(1) Absorption

Pharmacokinetic processes, including absorption, distribution, metabolism, and excretion, can lead to drug interactions, especially when the drug can cause changes in the concentration of one or more drugs in the plasma or tissues. Absorption refers to the process by which a drug enters the blood, which can be affected by intestinal peristalsis, gastric emptying, gastric pH, and gastrointestinal (GI) enzyme activity. Oral drugs are most affected by this, and their absorption speed and extent are related to the absorption activity of the gastrointestinal tract.

Drugs that accelerate gastric emptying, such as metoclopramide, can increase the amount of drugs entering the small intestine, the main absorption site of many drugs, and accelerate the absorption of substances such as cyclosporine. Reduced gastrointestinal motility can also shorten the time that intestinal epithelial cells are exposed to drugs, which leads to reduced absorption.

(2) Distribution

Drug distribution refers to the process by which absorbed drugs pass through the bloodstream to reach their site of action. The amount of the drug that finally reaches the site of the receptor in the tissue is determined by many factors, including plasma free (unbound) drug concentration, blood flow, and physical and chemical properties of the drug (such as lipophilicity, structural characteristics, etc.).

Psychiatric drugs must enter the central nervous system (CNS) through the blood-brain barrier to be effective. Lipophilic or fat-soluble drugs, such as benzodiazepines, neuroleptics, and cyclic antidepressants can penetrate the blood-brain barrier and can circulate more widely throughout the body than hydrophilic drugs such as lithium salts. In addition, drug transporters (such as P-glycoprotein) can regulate the permeability of intestinal epithelial cells, lymphocytes, renal tubules, biliary tract, and blood-brain barrier, and this effect can be involved in affecting the resistance and tolerance of certain drugs .

‍‍(3) Metabolism

Drug metabolism refers to the process of biotransformation of drugs into inactive or less active forms under the mediation of liver or small intestinal enzymes. Many clinically significant psychiatric drug interactions are based on metabolic processes. The metabolic process includes the first step of oxidation, reduction or hydrolysis, and the second step (the drug or the metabolite of the first step is covalently combined with glucuronic acid, sulfuric acid, glycine or glutathione to form a conjugate that is easily excreted) .

CYP450 isoenzymes are the most important enzymes in drug metabolism, including more than 30 types of heme-containing enzymes, mainly located in the endoplasmic reticulum of liver cells, involved in mediating the oxidative metabolism of multiple drugs and endogenous substances, more than 80% The metabolism of prescription drugs needs to be mediated by CYP450 enzymes. Among them, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 are important enzymes that catalyze the biotransformation of psychotropic drugs. Patients’ baseline CYP450 enzyme metabolic activity can be divided into four categories: poor, medium, normal, and ultra-fast, depending on the individual’s genetic susceptibility. Poor metabolism is related to specific drug interactions.

(4) Elimination

Drug excretion refers to a series of processes by which drugs are eliminated from the body. Many psychiatric drugs, such as antidepressants, anxiolytics, and antipsychotics, are mainly eliminated through liver metabolism, while lithium, gabapentin, and pregabalin are eliminated mainly through the kidneys. For patients with reduced baseline glomerular filtration rate, reduced renal elimination can lead to increased drug toxicity. In addition, conditions that can cause sodium deficiency, such as dehydration and the use of thiazide diuretics, can increase the reabsorption of lithium in the proximal renal tubules, leading to increased blood lithium levels and increased toxicity.

Drug interactions are widespread. Drug interactions include both the impact on combined medications and the effect on drug efficacy. Therefore, when developing new drugs, the risk of drug interactions should be closely assessed and monitored.

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