Pharmacokinetics is the study of a drug’s journey through the body, analyzing how a substance is absorbed, processed, and eliminated over time. These studies are a step in developing new medicines by providing a detailed picture of a drug’s behavior. By understanding this process, researchers can build a profile of a drug candidate’s safety and effectiveness before human trials.
The Purpose of Using Mouse Models
The development of a new drug begins with studies in animal models, and mice are a frequent choice for this early-stage research. These studies in rodents are integral to preclinical research, offering insights into how a drug candidate is handled by a living system before it is considered for human trials.
A primary reason for using mice is their physiological and genetic resemblance to humans. Many basic metabolic processes and organ systems in mice function in a way that can provide predictive data for how a drug might behave in people. This biological correlation allows scientists to investigate a compound in a system that, while not identical, is similar enough to offer valuable preliminary information.
Mice also offer practical benefits. Their small size means that only a small amount of a new, often rare and expensive, drug compound is needed for testing. Their rapid breeding cycle and relatively low housing costs make them a more economical option compared to larger animal models, allowing research teams to conduct multiple experiments efficiently.
The availability of genetically engineered mouse models allows for more targeted research. Scientists can use specific strains of mice, such as “knockout” mice where a particular gene has been inactivated, to mimic human diseases or genetic conditions. For example, a mouse model might be used that is deficient in a certain enzyme to see how that affects the drug’s metabolism, which helps investigate how a drug might perform in specific patient populations.
Key Pharmacokinetic Parameters Measured
Researchers measure specific quantitative data points to describe a drug’s behavior. These measurements are grouped under the acronym ADME, which helps organize the complex processes a drug undergoes from administration to elimination.
- Absorption describes how the drug moves from the site of administration into the bloodstream.
- Distribution refers to where the drug travels throughout the body’s tissues and organs after it has been absorbed.
- Metabolism is the process by which the body chemically modifies the drug, often in the liver, into substances called metabolites.
- Excretion is the removal of the drug and its metabolites from the body, through urine or feces.
To quantify these ADME processes, scientists measure several metrics from blood samples collected over time. One metric is the maximum concentration the drug reaches in the blood, known as Cmax. The time it takes to reach this peak concentration is called Tmax, and these two parameters provide a snapshot of how quickly a drug is absorbed.
Another metric is the drug’s half-life (t½), which is the time it takes for the drug’s concentration in the body to decrease by half. A short half-life might mean the drug is eliminated quickly and needs to be dosed more frequently. To understand the total exposure to a drug, researchers calculate the Area Under the Curve (AUC), which represents the cumulative concentration of the drug in the bloodstream over time.
Conducting a Mouse PK Study
A pharmacokinetic study in mice is a carefully planned procedure to generate precise data. The process begins with administering a calculated dose of the drug candidate to the mice. The method of administration is chosen to mimic how the drug might be used in humans, such as oral gavage to simulate taking a pill.
An intravenous (IV) injection may be used to deliver the drug directly into the bloodstream. This route ensures 100% of the drug enters circulation immediately. This provides a baseline against which other routes, like oral administration, can be compared to determine how much of the drug is successfully absorbed.
After administration, biological samples are collected at predetermined time points. This involves collecting small blood samples frequently at first—for instance, at 5, 15, and 30 minutes post-dose—and then less frequently over several hours. This timed collection is for accurately plotting the drug’s concentration as it rises and falls in the bloodstream.
The collected blood samples are processed to separate the plasma, which is then taken for bioanalysis. This final step uses sensitive analytical techniques, most often liquid chromatography with tandem mass spectrometry (LC-MS/MS), to measure the exact concentration of the drug in each sample. This technology can detect minute quantities of the compound, providing the precise data needed to calculate the pharmacokinetic parameters.
Interpreting and Applying the Data
Data from a mouse pharmacokinetic study guides decisions in the drug development process. These results provide the first in-depth look at how a potential medicine behaves in a living organism, and this information is used to predict its future performance and safety.
One application is informing the safe starting dose for first-in-human clinical trials. By using mathematical models and allometric scaling, which accounts for differences between species, scientists can extrapolate the mouse data to estimate a dose in humans that is likely to be safe and effective.
The PK data also reveals a drug’s potential liabilities. If a drug is metabolized too quickly (a short half-life) or is poorly absorbed when given orally (a low AUC), it may not be a viable product. This information allows medicinal chemists to modify the drug’s chemical structure to improve its properties.
Understanding a drug’s metabolism and elimination helps predict safety issues. If a drug is heavily processed by a specific enzyme in the liver, it could lead to drug-drug interactions if taken with other medications that use the same pathway. The data can also highlight if a drug or its metabolites are cleared by the kidneys, which could pose a risk to patients with impaired kidney function.