I need your opinion on ADMET properties. If one drug is a substrate of P-glycoprotein and also an inhibitor of P-glycoprotein1/2. Then what are the consequences of this behavior. Is this mix behavior is bad or good. Please give your reviews. Thanks
P- glycoprotei is a membrane efflux pump that extrudes xenobiotics/ endogenous substances out of the cell into the lumen or extracellular space. The drug-drug interactions through P-glycoprotein are affected by interindividual variations in drug bioavailability. They generally considered clinically insignificant unless the drugs also inhibit cytochrome P450 (which happens with a good number of foods and drugs). In theory a drug that is a substrate and inhibitor, it will reduce its extrusion from the cells.
The absorption of the drug in the gut will increase. Increasing its bioavailability and its inhibition of the P- efflux pump. The serum levels of the drug will increase but the cells in various parts of the body will not extrude the drug as efficiently. So the volume of distribution of the drug may increase. The drug may penetrate the blood brain barrier. This may result in increased adverse drug reactions, if the drug enters unintended target sites. Or therapuetic effect if the target is the CNS or target tumor with the efflux pump. An already widely distributed drug may result increased free drug that may be rapidly metabolized or excreted.
On the other hand, the drug that had increased volume of distribution may reduce the concentration of free drug and therefore reduce the drug metabolism and excretion. Depending of the form and site of excretion Of the drug. Metabolism is impacted most for drugs that inhibit both P-glycoprotei and CYP450, because serum levels may be raised while metabolism is reduced. Which may lead to toxicity. This may not be the case for drugs that are still metabolized at a normal rate or excreted unchanged.
The kidneys do excrete a few substaces via P-glycoprotein efflux pump. So inhibition of the pump would reduce the excretion of the drug by the kidneys (assuming it remains unchanged or its metabolite is still a substrate of the efflux pump). However, excretion that is not dependent on the pump will not be affected.
In a nut shell, the drug that is a susbsrate (uses) the efflux pump and the inhibits P-glycoprotein, the most likely pharmacokinetic parameters to be affected are absorption, distribution and excretion. Whether the effect of this inhibition of the pump will be negative or positive depends on whether the drug also inhibits enzymes involved in its metabolism, drug interactions, food interactions, its therapeutic index, acess to sites that the drug may cause harm or benefit, and site of excretion.
The outcome may be good, bad or have no clinical effects at all. The specific drugs would have to be considered individually to determine the impact of the efflux pump inhibition. In some cases drugs are administed with an efflux pump inhibitor to maintain appropriate drug concentration at the target site. This article is quite useful.
Article P-glycoprotein and its role in drug-drug interactions
ADMETox property is important to validate the molecule to be consider as Drug. Lipinski Rule of 5 gives you the value of the molecule, they are very important to consider for Molecular Docking. For more information, Read the followings,
http://www.scfbio-iitd.res.in/software/drugdesign/lipinski.jsp
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/lipinskis-rule-of-five
Article BDDCS, the Rule of 5 and drugability
Thanks & Regards.
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