Different pharmacokinetics of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-(3-14C)dithiazocine-4-carboxyli c acid between the fasting and non-fasting rat: role of intestinal microorganisms.
1. We report differences in the pharmacokinetics of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-(3-14C)dithiazocine-4-carb oxylic acid (14C-SA3443) between the normal fasting and non-fasting rat, especially in the blood concentration-time curves and respiratory excretion. Exhalation of 14CO2 was an important route of elimination and accounted for 21.2% of the dose in the non-fasting rat but only 3.7% in fasting animals. 2. In the intestinal microorganism-compromised rat, we found little differences in the pharmacokinetics of 14C-SA3443 between fasting and non-fasting states. No respiratory excretion was observed in the intestinal microorganism-compromised animal. 3. In the reaction mixture of 14C-SA3443 with the cecal contents of rat, 14C-acetic acid and 14C-butyric acid were detected and 14CO2 barely detected. 4. The amounts of 14C-acetic acid and 14C-butyric acid in the reaction mixture of 14C-SA3443 with non-fasting rat cecal contents were more than those with fasting rat cecal contents. 5. We concluded that the reason for the different pharmacokinetics of 14C-SA3443 between the fasting and non-fasting rat was the differences in participation of the metabolism of 14C-SA3443 by intestinal microorganisms.
Tsuji
F
F
Discovery Research Division, Santen Pharmaceutical Co., Ltd, Osaka, Japan.
Morikawa
N
N
Takashina
H
H
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001392:Azocines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002432:Cecum / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D002851:Chromatography, High Pressure Liquid; D004220:Disulfides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005215:Fasting; D005243:Feces; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000382:microbiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D001392:Azocines; D002250:Carbon Radioisotopes; D004220:Disulfides; C069788:SA 3443