ORII Takao Dept. of Pharmacy, Univ. of Tokyo Hospital, Assis. Professor, 医学部・附属病院, 助手 (50231246)
SATO Hitoshi Dept. of Pharmacy, Univ. of Tokyo Hospital, Assoc. Professor, 医学部・附属病院, 助教授 (40187224)
SAWADA Yasufumi Faculty of Pharmaceutical Sciences, Kyushu Univ., Professor, 大学院・薬学研究科, 教授 (80114502)
NAKANO Shigeyuki Faculty of Medicine, Ohita Medial Univ., Professor, 医学部, 教授 (10033341)
HIGUCHI Shun Faculty of Pharmaceutical Sciences, Kyushu Univ., Professor, 大学院・薬学研究科, 教授 (40218699)
大江 和彦 東京大学, 医学部・附属病院, 教授 (40221121)
|Budget Amount *help
¥32,700,000 (Direct Cost: ¥32,700,000)
Fiscal Year 1999: ¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 1998: ¥20,300,000 (Direct Cost: ¥20,300,000)
1) Mechanism of drug interactions : Drug-grape fruit juice (GFJ) interaction studies were undertaken to clarify the mechanism of drug interactions at the gut tissue. We have found that a GFJ component, dihydroxy vergamotine, inhibited the efflux activity of P-glyco-protein. It was thus suggested that, according to this inhibitory mechanism on Pglycoproptein as well as on P450 enzymes, GFJ enhances the drug absorption of drugs, by which plasma concentrations of drugs may inrease.
2) Establishment of a prediction method of drug interactions in preclinical phases and dose setting for clinical trials : Modelling analysis was carried out to predict drug interactions quantitatively, using a Ca-blocker, felodipine, and an immunosuppresant, cyclosporine, as model compounds. We attempted to predict the contributions of the liver and gut in drug interactions based on clearance theory from in vivo and in vitro experiments using rats. As a result, it has been successful to predict the increase in d
rug concentrations in blood by calculating drug concentrations in the liver and gut using a new method of predicting inhibitor concentrations in these tissues. Moreover, it has become possible in this study to estimate the increase in drug concentrations in blood in humans when an inhibitor is coadministered.
3) Investigation of genetic polymorphism : With regard to CYP2C19, we found that the clearance value of people showing wt/m1 and wt/m2, which have been conventionally classified as extensive metabolizer (EM), falls between the clearance values in EM and poor metabolizer (PM), indicating that heterozygous polymoriphisms lead to the reduction of metabolic activities. In patients with gastric ulcer, clinical effect (examination of ulcer improvement using an endoscope) of omeprazole, given at regular doses indicated in drug labelling, was 83% for PM and 32% for EM, which should be the manifestation of reduced clearance in PM. The short period of time required for ulcer healing was also shorter in PM.
4) Construction of information on dose settings and choice of medicine to avoid interactions of drugs in the market : We conducted a retrospective survey of clinical cases for drug interactions, and established a dose setting method, be used alternatively for particular drugs which may interact with co-administered drugs.
5) Development of software to search drug information on drug interaction avoidance : We created a database of drug information on drug interactions, by which we can rapidly search the combination of drug interactions. Software for personal computers was then implemented to analyze possible drug interactions based on the above database, which can be easily utilized in clinical settings.
6) Establishment and evaluation of an order entry system to provide drug information on drug interactions : By incorporating the above mentioned software into the conventional order entry system, we developed an order entry/prescription auditing system for drug interactions in the University of Tokyo Hospital. Less