Pharmacokinetics of gamma-hydroxybutylic acid (GHB) and gamma-butyrolactone (GBL), the anti-angiogenic metabolites of oral fluoropyrimidine UFT, in patients with gastric cancer.
Gamma-hydroxybutylic acid (GHB) and gamma-butyrolactone (GBL), the metabolites of UFT, which is an oral fluoropyrimidine, have been reported to inhibit angiogenesis with IC50 values of 25.8 ng/ml. The pharmacokinetics of GHB and GBL were examined after the administration of UFT in patients with gastric cancer. The patients received 200 mg of UFT orally twice a day. Peripheral blood samples were collected at 0, 0.5, 1, 2 and 4 hr after the time of dosing on day 5. The baseline and endogenous GBL concentrations in plasma were 20.2 +/- 7.5 ng/ml for patients and 16.8 +/- 4.0 ng/ml for volunteers (P = 0.221). The values of C(max) for tegafur, uracil, 5-FU and GBL were 14.7 +/- 5.2 and 4.0 +/- 2.8 microg/ml, 191.2 +/- 115.3 and 147.5 +/- 57.3 ng/ml, respectively, and the values of Tmax were 1.0 +/- 0.6, 1.1 +/- 0.6, 0.9 +/- 0.6 and 1.2 +/- 0. 6 hr, respectively. The concentration of GBL was much higher than its IC50 value for angiogenesis. GBL is thus suggested to contribute to the anticancer effects of UFT in addition to that of 5-FU, which is continuously metabolized from UFT.
Emi
Yasunori
Y
Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Sumiyoshi
Yasushi
Y
Oki
Eiji
E
Kakeji
Yoshihiro
Y
Fukui
Yousuke
Y
Maehara
Yoshihiko
Y
D015107:4-Butyrolactone / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000378:metabolism*; D005641:Tegafur / Q000008:administration & dosage / Q000378:metabolism*; D014498:Uracil / Q000008:administration & dosage / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004338:Drug Combinations; D006885:Hydroxybutyrates; C096910:UFT(R) drug; D005641:Tegafur; C111420:4-hydroxybutyric acid; D014498:Uracil; D015107:4-Butyrolactone