IT MAY BE MICROSOMAL ENZYME INVOLVED IN THE METABOLISM

Hello Bishnu Prasad Behera

It could be stress associated with chronic drug delivery to animals that can influence several physiological processes. So, designing a reliable voluntary oral drug delivery method becomes essential.

Oral gavage is a widely used technique for the administration of precise doses of drugs. A skilled operator needs few seconds to perform this technique correctly, but someone who is not entirely confident in their animal handling skills will take much longer, leading to distress for both mice as well as the operator.

You could compound the drug in rodent food or dissolve it in water. These approaches also have limitations as they are affected by drug stability at room temperature for extended periods of time, the drug's solubility in water, and that the dosing is highly dependent on timing of food or water intake.

You may want to refer to the article attached below which describes how to voluntarily administer substances orally in a time- and dose-controlled manner to laboratory mice. This would minimize injury potential and stress often associated with the commonly used gavage technique. You could incorporate the drug into artificially sweetened and flavored jelly and give to mice previously trained to eat the jelly.

Article Method for voluntary oral administration of drugs in mice

This approach of administering the drug to mice orally might help!

Best.

Dear Bishnu Prasad Behera,

There may be many reasons, it is not necessarily surprising.

One is PK, in the mouse compound may have lower bioavailability or higher clearance leading to low exposure. As suggested by Vijayakumar A R metabolism may be faster in the mouse leading to the high clearance.

Even with similar intrinsic enzyme activity elimination is faster in mouse due to higher blood flow / kg body mass. Following simple allometry principles a much higher mg/kg dose is expected to be required in mouse compared to human.

Is your treatment acute (single dose) or chronic? Due to faster elimination in the mouse residence time will be lower, you may need to administer more often in the mouse than in human.

Another reason, sometimes overlooked, is pharmacology. Is the target affected by the drug present in mouse? Is it having the same biological role in mouse as human (or are there redundant mechanisms in mouse not present in human leading to different sensitivities of the efficacy model)? Is your drug having the same potency in the mouse target as the human target?