Pharmacokinetics and safety of JTE-522, a novel selective cyclooxygenase-2 inhibitor, in healthy male volunteers.
OBJECTIVE
The pharmacokinetics and safety profile of JTE-522, 4-(4-cyclohexyl-2 methyloxazol-5-yl)-2-fluorobenzensulphonamide, a novel selective cyclooxygenase-2 inhibitor were investigated in healthy male volunteers.


METHODS
Initially, as a pilot study, five groups of two subjects were given oral doses of 3-100 mg of JTE-522. After safety assessment, subjects were given 150 and 200 mg of JTE-522. The effect of food-intake on the pharmacokinetics of JTE-522 at a dose of 150 mg was examined. In the multiple-dose study, subjects were given 150 mg of JTE-522 once a day for 7 days. Concentrations of unchanged JTE-522 in plasma, blood and urine were determined by high performance liquid chromatography (h.p.l.c.). Concentrations of metabolites were estimated with h.p.l.c. chromatograms and calibration curves for quantification of unchanged JTE-522.


RESULTS
In the course of this study, no serious abnormality attributable to the test drug was observed, suggesting that JTE-522 was well tolerated in healthy subjects. In a single-dose study, the concentrations of JTE-522 in blood were much higher than the corresponding concentrations in plasma. JTE-522 was readily distributed to blood cells and percentage distribution into blood cells was more than 99.0%. However, the values of Cmax in blood at doses of 100, 150, 200 mg JTE-522 were 15241, 20445 +/- 3918 (16333-24556), 20965 +/- 3260 (17544-24386) ng ml-1, respectively. These findings suggest that JTE-522 has a high affinity for blood cells and the distribution into blood cells is limited at the higher doses of over 100 mg. In a multiple dose study, pharmacokinetic parameters including t1/2 and AUC after the fourth administration were comparable with that of the seventh administration. Thus, these findings suggest the absence of accumulation on the multiple-dosing of JTE-522.


CONCLUSIONS
These results indicate that JTE-522 has an acceptable pharmacokinetic profile for clinical use without any serious adverse events as we verified in healthy young male volunteers.
Ikeda
Yasuhiko
Y
Department of Pharmacology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192 Japan. yasuhiko@hama-med.ac.jp
Umemura
Kazuo
K
Kondo
Kazunao
K
Nakashima
Mitsuyoshi
M
Kobayashi
Takuo
T
Takahashi
Mitsuru
M
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins; D010080:Oxazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010865:Pilot Projects; D011451:Prostaglandin-Endoperoxide Synthases; D000096926:Benzenesulfonamides
D001557:Benzenesulfonates; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D010080:Oxazoles; D011451:Prostaglandin-Endoperoxide Synthases; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C496540:PTGS2 protein, human