The absorption and excretion of paeoniflorin after intravenous and oral administration was studied in rats to evaluate the significance of paeoniflorin in the pharmacological action of Paeony root. The plasma concentration of paeoniflorin after intravenous administration at the doses of 0.5, 2.0 and 5.0 mg kg-1 rapidly decreased, simulated by a biexponential curve, with mean terminal half-lives of 11.0, 9.9 and 12.6 min, respectively. The Vdss values were 0.332, 0. 384 and 0.423 L kg-1 and the CLtot values were 26.1, 31.2 and 30.3 mL min-1 kg-1 at each dose. When given orally at the same doses, the absolute bioavailability values (F) determined by the AUC were 0.032, 0.033 and 0.038, respectively. The cumulative urinary and faecal excretions of paeoniflorin at the dose of 5 mg kg-1 after intravenous administration were 50.5 and 0.22% of the dose within 72 h, and 1.0 and 0.08% of the dose after oral administration within 48 h, respectively. Cumulative biliary excretion after intravenous or oral administration at a dose of 0.5 mg kg-1 was 6.9 and 1.3% of the dose within 24 h, respectively. The total CLR and CLB value after intravenous dosing was less than the CLtot value. These findings suggest that paeoniflorin is metabolized in other organs as well as in the liver. We conclude that paeoniflorin absorbed is excreted mainly in urine, it has a low bioavailability and the metabolites may be involved in the pharmacological action of Paeony root.

We explored the possible role of the specific regions in the brain stem on the antinociceptive actions of mesaconitine (MA) and benzoylmesaconine (BM) by the microinjection of MA and BM into nucleus reticularis paragigantocellularis (NRPG), nucleus raphe magnus (NRM), and periaqueductal gray (PAG). MA microinjected into NRPG, NRM, or PAG elicited a dose-dependent antinociceptive action, whereas BM injected into NRM or PAG elicited a dose-dependent antinociceptive action but not in NRPG. The NRM appeared to be the most sensitive region among the three tested locations.

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.

Tsumura-shuchi-bushi-matsu (TJ-3021) is a processed Aconiti tuber which has a potent antinociceptive action. The present study was undertaken to study the analgesic mechanism produced by TJ-3021. RCS (repeated cold stress) rats in hyperalgesia were markedly suppressed by oral administration of TJ-3021. Intrathecal and intraperitoneal administration of a selective alpha 2-adrenoreceptor antagonist, idazoxan (IDA), reduced significantly the analgesic effect of TJ-3021 in RCS rats. Methysergide (METH), a 5-HT receptor antagonist, demonstrated a similar effect, while intraperitoneal administration of opioid receptor antagonist, naloxone, did not produce the effect. Both oral and intracisternal administration of mesaconitine (MA) which is one of the main potent alkaloids contained in TJ-3021 produced analgesic effect in non-RCS rats.

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