Observation of Movement of Drug-transport Molecules through Biliary Excretion using PET
-Analysis of in vivo drug delivery and establishment of a quantitative evaluation method -

◇Points

• The first time to kinetically analyze drug distribution to whole body tissue and the elimination process using positron emission tomography (PET).
• Successful visualization of the elimination process via the drug transporter "Mrp2".
• Nomination of the PET probe for the analysis of "Mrp2" as a diagnostic agent for hepatobiliary transport function.

　RIKEN (Ryoji Noyori, President) has successfully observed the function of Mrp2, which is one of the key drug transporters, and is related to the excretion of drugs or endogenous substances into bile, using Positron Emission Tomography (PET). In addition a new analytical method has been developed to quantitatively evaluate the pharmacokinetics of the drug. This has been achieved by researcher Tadayuki Takashima, et al., of the Molecular Probe Dynamics Laboratory (Yasuyoshi Watanabe, Team Leader), Center for Molecular Imaging Science (Yasuyoshi Watanabe, Director).
　　　Pharmacokinetic study investigates the movement of drugs in vivo, and is one of the important studies in drug discovery and development for finally discovering "the drugs gentle on the patient" with fewer side-effects. On the other hand, PET can directly obtain pharmacokinetic information based on drug concentration in the tissues and has gained much attention recently in the pharmacokinetic research field. However, previously applied cases were limited to reports of functional analysis of the drug transporter P-glycoprotein which functions to protect the brain from xenobiotics such as drug agents. This was due to the fact that PET probes to evaluate the function of a drug transporters other than P-glycoprotein have not been reported, and an accurate evaluation of these transporters could not be carried out.
　　　This research team focused on "Mrp2" drug transporter in hepatobiliary transport, in order to observe drug distribution to whole body tissue and the elimination process. Mrp2 has been known to be involved in the hepatobiliary elimination of many drugs, especially anionic drugs, and hereditary diseases such as jaundice. Thus, Mrp2 is one of the extremely important proteins in pharmacokinetic research. A wild type rat with normally functioning Mrp2, and a mutant type rat with a Mrp2 deficient gene were prepared and observed using the PET probe, 15R-[¹¹C]TIC-Me, which was constructed to study Mrp2 function. As a result, it could be learned that the distribution of the radioactivity derived from 15R-[¹¹C]TIC-Me to whole body tissues and its elimination process were completely different between normal rats and mutant rats. These results show that Mrp2 function in tissue uptake and excretion could be quantitatively evaluated using the numerical values (clearance) by PET image analysis with 15R-[¹¹C]TIC-Me.
　　　In the future, the feasibility of the use of 15R-[¹¹C]TIC-Me will be considered in a human clinical study, as a diagnostic agent of hepatobiliary transport function. Moreover, the prediction of the drug-drug interaction with the other drugs, such as pravastatin (cholesterol-lowering agent) which is mainly transported by Mrp2, as well as possible side-effects and the change in drug efficacy due to Mrp2 mutation caused by genetic polymorphism, and the effective utilization of predictive studies on the pharmacokinetics related to Mrp2, are expected.

The achievements of this study were published in the U.S. science magazine Journal of Pharmacology and Experimental Therapeutics, November 2010 vol. 335 no. 2 314-323.