Reveal the Mechanism of Pharmacokinetics
Mitsuru Sugawara , Professor
Faculty of Pharmaceutical Sciences/Graduate School of Life Sciences (School of Pharmaceutical Sciences and Pharmacy)
High school : High school: Takigawa High School (Hokkaido)
Academic background : Hokkaido University Graduate School of Pharmaceutical Sciences
- Research areas
- Pharmaceutics, Pharmacokinetics
- Research keywords
- Pharmacokinetics, Drug Metabolism, Digestive Tract, Pharmaceutical Production, Medical Sociology
What is your objective?
Figure 1 Diagram of pharmacokinetics
The administered medicine is absorbed, enters the blood, and is distributed throughout the body. It undergoes metabolization and inactivation through conjugation in the liver, filtration, secretion, and reabsorption through the kidneys, and is finally excreted through urine or bile.
At our laboratory, we are conducting research on pharmacokinetics. Pharmacokinetics is the activity of medicinal chemicals in the body that includes absorption (the process in which medicine enters the body), distribution (the process in which medicine is carried through the blood and is brought to the organs), metabolization (the process in which medicine is detoxified – such as by the liver), and excretion (the process in which medicine or the metabolite leaves the body through urine or feces) (Figure 1). This can be said to be the method in which the body processes medicine.
Many of the "effects" or "side effects" of medicine are related to the concentration of medicine in the body. The degree of concentration of medicine in the body can be shown by the amount of medicine concentrated in the blood. Therefore, by explicating the pharmacokinetic mechanism for absorption, distribution, metabolization, and excretion, and controlling the medicine's blood concentration, it is possible to safely and effectively use medicine. Pharmacokinetics can also vary for individuals, so depending on the medicine, even if the same amount is used (taken orally or administered by syringe) it does not always result in the same blood concentration. It is believed that if the reasons for this individual variance can be discovered, it would be possible to develop pharmacotherapy customized for individual patients (individualized pharmacotherapy).
Therefore, we are hoping to contribute to the formulation of effective pharmacotherapy by (1) discovering the relationship between the blood concentration of a medicine and its "effects" and "side effects," and (2) discovering the factors (mechanisms) that cause the individual variance in pharmacokinetics from the viewpoint of a patient's physiological changes or genetics factors.
What sort of experiments are you conducting?
Photo 1 Measuring device for medicine concentration
To measure the medicinal blood concentration, we use an analyzing device called a high-performance liquid chromatograph (HPLC) (Photo 1). Because this device selects the ideal detector out of multiple detectors with different principles of measurement depending on the physiochemical properties or the concentration of the medicine to be measured, it is widely used for measuring medicine concentration.
The test blood used in research is obtained either from animals that have been fed or injected with medicine, or from patients.
One example of our research results is as follows: Figure 2 shows the relationship between the blood concentration of a specific antibiotic and the clinical effect (sanitization effect). Although details are omitted, it is clear that within four days after the initiation of administration (that is to say, early on), the faster the blood concentration reaches the target level, the more cases of sanitization and decrease in bacteria are observed, and the more effective the medicine. On the other hand, Figure 3 shows the relationship between dosage (intravenous drip infusion) and the blood concentration. You can see that the greater the dosage over 2 days, the higher the blood concentration. Taking the above sanitization effect into account, it can be concluded that in order to achieve sufficient blood concentration levels early on, a 2-day dosage of 1,600 mg or higher is ideal.
In order to discover the detailed mechanisms of absorption, distribution, metabolization, and excretion, molecular biological methods like cell cultivation or gene expression are used. For example, in order to examine the details of the medicine absorption mechanism of the digestive tract or the medicine metabolization mechanism of the liver, it is very helpful to use cultivated cells from the intestines or liver to examine the mechanism of how medicine enters or exits cells, and what sort of reaction the medicine undergoes to be metabolized in the cell under that process. In addition, when further examining the function of membrane proteins (transport carriers) and metabolic enzymes involved with the cell membrane permeation of medicine, we introduce the related gene into cells and create an expression system or suppress the gene that is already expressed.