| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Research Abstract |
Aim #1 : We determined whether the two probe drugs, caffeine and phenytoin, could be simultaneously administered as a cocktail test to estimate three cytochromes P450 (CYP1A2, 2C9 and 2C19), N-acetyltransferase (NAT2), xanthine oxidase (XO) and flavin-containing monooxygenase (FMO) enzyme activities in vivo. in 1999.
Methods : Twenty-nine healthy volunteers (14 men and 15 women) received orally 150 mg of caffeine and 100 mg of phenytoin separately and in combination using a 3x3 Latin square. The activities of CYP1A2, NAT2 and XO were expressed by urinary caffeine metabolic ratios, and those of CYP2C9 and 2C19 by phenytoin chiral metabolite ratios.
Results : Ascertaining the separate and cocktail phenotyping tests for caffeine correlated with each other, but that for phenytoin did not.
Aim #2 : Based on the results of Aim #1, caffeine phenotyping test was extended to assess in vivo activities of five drug-metabolizing enzymes, CYP1A2, NAT2, XO, FMO and CYP2A6 in Kyushu, Japan, in 2000.
Methods : One hundred eighty-two healthy volunteers (108 men and 74 women) received an oral 150-mg dose of caffeine before sleep, then overnight urine sample was collected and the concentrations of caffeine and its metabolites were analyzed by HPLC.The enzyme activities were expressed by urinary caffeine metabolic ratios.
Results : Frequency distributions of CYP1A2, FMO, and CYP2A6 activities were unimodal, whereas those of NAT2, and XO activities were trimodal and bimodal, respectively. The CYP1A2 activity was statistically higher in smokers than in non-smokers (p<0.0001). The frequency of slow acetylators was 11%. The activities of CYP1A2 and XO were statistically higher (p<0.01), and that of NAT2 was lower (p<0.02) in males than in females. A few subjects showed significantly low activities of CYP1A2, XO, FMO, and CYP2A6. We are currently determining the genotypes of these enzymes and will determine the therapeutic relevance.
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