Scientists Develop New Method for Determining Intracellular Bioavailability

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The new label-free method for quantifying intracellular bioavailability can be used to predict drug exposure to target cells and hence its efficacy.

Evaluating a drug’s efficacy in the body requires taking into account factors that influence the internal environment of cells as most drug targets are located inside the cell. One of the main challenges in early drug discovery is achieving sufficient drug levels within the target cells. The ability to measure the amount of drug locally available to bind intracellular targets is, therefore, crucial for identifying a lead candidate. However, methods for determining intracellular drug levels are lacking.

A group of researchers recently published a new label-free method for quantifying intracellular bioavailability, which could be used to predict exposure of small molecules to the target cells and hence the drug’s efficacy. The method is based on measuring the concentration of unbound drug available to exert a therapeutic effect inside the cell. It takes into account drug molecules that bind to various cell components, which are then unavailable and unable to exert its intended effect. The researchers demonstrated that by using this new method to measure intracellular bioavailability, it is possible to predict the effects of the drug in various more advanced cell models for specific therapeutic areas, such as cancer, inflammation, and dementia. 

The method is also being investigated for its potential to predict drug efficacy in the body. Systemic bioavailability, defined as the amount of drug in the blood, may not accurately correlate to a therapeutic effect because the proportion of drug entering the target cell could be higher or lower than that in blood. For example, if the drug molecules bind to other cellular components, get metabolized, or are transported out of the cell, the available fraction of drug inside the cell will be reduced (i.e., intracellular bioavailability will be lower and there are less free drug molecules available to exert its pharmacological action). Correction factors must, therefore, be introduced in pharmacokinetic studies.


“Our preliminary studies show that replacing the correction factors with a simple determination of local bioavailability in the cells seems to be possible,” Professor Per Artursson, who is heading the study, commented in a press release. “But more experiments are required before we know how applicable our principle is at tissue and organism level. Clearly, intracellular bioavailability is on the way to becoming an important early instrument in pharmaceutical drug research.”

Source: Uppsala University, PNAS