Mass balance study of [14C] rabeprazole following oral administration in healthy subjects.
The study was designed to determine the excretion balance of radiolabeled rabeprazole in urine and feces and to examine the metabolite profile in plasma, urine and feces after a single oral dose of [14C] rabeprazole, preceded by once daily dose of rabeprazole for 7 days. Six healthy subjects were enrolled in this study. The study was a single-center, open-label, multiple-dose, mass-balance study. Each subject received a single 20 mg dose of rabeprazole tablet for 7 days followed by the administration of 20 mg of [14C] rabeprazole as an oral solution after an overnight fast on Day 8. After oral dosing of [14C] rabeprazole, the mean Cmax of total radioactivity was 1,080 +/- 215 ng equivalent/ml with 0.33 +/- 0.13 hours of the mean tmax. The apparent elimination half-life of total [14C] radioactivity was 12.6 +/- 3.4 hours. The total [14C] recovery in urine and feces was 99.8 +/-0.7% by 168 hours after oral administration of [14C] rabeprazole, and mean cumulative [14C] radioactivity excreted in urine was 90.0 +/- 1.7% by 168 hours and 79.8 +/- 2.5% of the radioactivity was excreted in urine within 24 hours. Excretion via feces added to the total by 9.8%. The major radioactive component in the early plasma samples was rabeprazole, however the thioether and thioether carboxylic acid metabolites were the main radioactive components in the later plasma sample. These results support the previous finding that the substantial contribution of the non-enzymatic thioether pathway minimizes the effect of CYP2C19 polymorphism on the inter-individual variation ofplasma clearance of rabeprazole compared with other PPIs. Low levels of the sulfone metabolite were detected only in early plasma samples. No rabeprazole was detected in any urine and feces samples. The main radioactive components in urine were thioether carboxylic acid and mercapturic acid conjugate metabolites, and in the feces, the thioether carboxylic acid metabolite. The administration of [14C] rabeprazole was safe as evidenced by the lack of serious adverse events and the fact that all observed events were mild in intensity. [14C] rabeprazole was rapidly absorbed after oral administration and mostly excreted in urine.
Setoyama
T
T
Preclinical Development, Eisai Research Institute of Boston, Inc., 1 Corporate Drive, Andover, MA 01810, USA. tsutomu_setoyama@eisai.com
Drijfhout
W J
WJ
van de Merbel
N C
NC
Humphries
T J
TJ
Hasegawa
J
J
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000284:Administration, Oral; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002250:Carbon Radioisotopes; D002264:Carboxylic Acids / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D064750:Rabeprazole; D013440:Sulfides / Q000378:metabolism
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D002250:Carbon Radioisotopes; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D013440:Sulfides; D064750:Rabeprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D006180:Proton-Translocating ATPases