Research Projects

1. Functions and regulation mechanisms of transporters involved in drug disposition
2. Roles of transporters in drug disposition
3. Physiological and pathophysiological roles of transporters
4. Methodologies of evaluation and prediction of drug disposition


Research Interests

The processes of drug disposition in the body (absorption, distribution, metabolism and excretion) are important as factors that determine drug concentration at the site of action and, thereby, affect therapeutic effects and also adverse effects.  We have been particularly interested in transporters (membrane proteins for solute transport) involved in the processes of absorption, distribution and excretion of drugs and studying their functions and roles in drug disposition.  Accumulating information about transporters would help exploring possibilities that transporters might be utilized for drug delivery into the body and/or to specific organs.  It would also help exploring strategies to, taking into account interindividual differences, adjust dosage regimens and optimize drug therapies.  

Transporters may play important roles in pathophysiological events as well as in physiological events and, hence, could be targets of drug development.  Therefore, we have also been studying the functions and roles of transporters from physiological and pathophysiological viewpoints.  

Factors involved in drug disposition can be examined by various evaluation methods for drugs and candidates.  Predicting drug disposition based on the results of such examinations would allow making the processes of drug development and optimization of drug therapies more focused and efficient.  In order to facilitate that, it is important to develop and improve methods of evaluation and prediction.  We have also been interested in that.  Particular emphases have been placed on the evaluation of membrane transport, including that by transporter, and quantitative prediction of drug disposition utilizing pharmacokinetic methods.  


Table 1.  Major transporters of interests.  

Transporter	Description
PCFT (proton-coupled folate transporter)	Transporter responsible for the intestinal absorption of folate (vitamin B9) and also involved in the absorption of antifolate drugs, such as methotrexate
MATE (multidrug and toxin extrusion protein)	Transporter involved in the renal secretion (excretion) of cationic compounds, including drugs
RFT (riboflavin transporter)	Transporter involved in the intestinal absorption of riboflavin (vitamin B2)
SNBT (sodium-dependent nucleobase transporter)	Transporter involved in the intestinal absorption of nucleobases and derivatives
Aquaglyceroporin	Transporter involved in the transport of glycerol and small water-soluble solutes in various organs

Fig. 1.  Intestinal drug absorption mediated by PCFT.        MTX, an antifolate drug, is absorbed via PCFT, which is present in the intestine for the absorption of folate (vitamin B9).  Although about 70% of its oral dose is absorbed from the intestine, it is not absorbed in the lower part, where PCFT is not present.

Fig. 2.  Assay method for the evaluation of the functionality of MATE.        DAPI, a fluorescent dye used for nuclear staining, can be transported by MATE, which is involved in the renal secretion (excretion) of cationic compounds, including drugs, but this compound is practically impermeable through the plasma membrane of most live cells.  Taking advantage of such transport characteristics and fluorescent nature, which makes it easier to detect, DAPI can be utilized for rapid assays of the functionality of MATE.  Incubation of regular cultured cells (mock), which do not have MATE, in DAPI solution does not result in any fluorescent emission, but incubation of those transfected with hMATE1, a human MATE subtype, results in the emission of blue fluorescence from DAPI, which is transported into the cells and bound to nuclear DNA.