In-vivo assessment of extrahepatic metabolism of paeoniflorin in rats: relevance to intestinal floral metabolism.
The extraction ratios of paeoniflorin in gut wall (EG), liver (EH) and lung (EL) were assessed by comparing AUCs after various routes of its administration to estimate the first-pass effects and the metabolism by intestinal flora. Pulmonary extraction ratio of paeniflorin was assessed by comparing AUCs calculated from venous and arterial plasma concentrations after its intravenous administration (0.5 mg kg-1). The mean pulmonary extraction ratio was estimated to be 0.06. The hepatic extraction ratio (EH was assessed by comparing AUCs after intraportal and intravenous administrations (0.5 and 5 mg kg-1). The plasma concentration profiles of paeoniflorin after intraportal administration were very close to those after intravenous administration, suggesting a negligible hepatic extraction ratio of paeoniflorin. The AUC value after intraperitoneal administration (0.5 mg kg-1) was greater than that after intraportal or intravenous administration. This finding suggests that paeoniflorin is not metabolized in the gut wall. The transference of paeoniflorin from the serosal side to the mucosal side was evaluated by the in-vitro everted sac method. The low intestinal permeability (19.4% at 60 min) was demonstrated by the comparison with phenobarbital (63.1% at 60 min). We conclude that paeoniflorin is not metabolize by gut wall, liver and lung, its poor absorption from the intestine results in extremely low bioavailability and the unabsorbed fraction of paeoniflorin is degraded by the intestinal flora.
Takeda
S
S
Drug Safety and Metabolism Department, Tsumura Central Research Laboratories, Tsumura & Co., Ibaraki, Japan.
Isono
T
T
Wakui
Y
Y
Mizuhara
Y
Y
Amagaya
S
S
Maruno
M
M
Hattori
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D001419:Bacteria / Q000378:metabolism*; D001565:Benzoates; D001682:Biological Availability; D001952:Bridged-Ring Compounds; D005960:Glucosides / Q000008:administration & dosage / Q000378:metabolism*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology; D008168:Lung / Q000378:metabolism; D008297:Male; D039821:Monoterpenes; D051381:Rats; D017207:Rats, Sprague-Dawley; D006027:Glycosides
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D001952:Bridged-Ring Compounds; D005960:Glucosides; D039821:Monoterpenes; C015423:peoniflorin; D006027:Glycosides