Oral administration of raffinose, a naturally occurring indigestible oligosaccharide, has reportedly ameliorated atopic dermatitis in human subjects although the mechanism is unknown. The present study investigated the effect of dietary raffinose on allergen-induced airway eosinophilia in ovalbumin-sensitised Brown Norway rats as an atopic disease model. Brown Norway rats were immunised by subcutaneous injection with ovalbumin on day 0 and fed either a control diet or the diet supplemented with raffinose (50 g/kg diet). The rats were exposed to aerosolised ovalbumin on day 20, and broncho-alveolar lavage fluid was obtained on the next day. The number of eosinophils in the fluid was significantly lower in the rats fed the raffinose diet than in those fed the control diet. Dietary raffinose significantly reduced IL-4 and IL-5 mRNA levels in lung tissue and tended to lower ovalbumin-specific Ig E levels. Suppression of eosinophilia by dietary raffinose was still observed in caecectomised and neomycin-administered rats, suggesting little contribution by the colonic bacteria to the effect of raffinose. Intraperitoneal administration of raffinose also suppressed eosinophilia. Significant concentrations of raffinose were detected in portal venous and abdominal arterial plasma after the intragastric administration of raffinose. Overall, the findings suggest that dietary raffinose ameliorates allergic airway eosinophilia at least partly via post-absorptive mechanisms in Brown Norway rats.Raffinose: Eosinophilia: Allergy: Ovalbumin: Broncho-alveolar lavage fluid
Focusing on the disposition of cyclosporin A (CsA) in the liver and intestine, effects of gentamicin-induced acute renal failure (ARF) on the decreased oral bioavailability of CsA were evaluated in rats. The area under the CsA concentration-time curve (AUC) in ARF rats after oral administration (5 mg/kg) significantly decreased by 43% as compared to the control, while the apparent oral clearance significantly increased by 76% of the control. The portal AUC of CsA in ARF rats with bile flow decreased by 67% as compared to the control rats. Without bile flow, the portal AUC of CsA in control rats decreased by 50% as compared to those with bile flow, whereas ARF rats without bile flow showed no notable change as compared to those with bile flow. The AUC of CsA mono-oxidative metabolite via CYP3A (M-OH) in ARF rats after oral or intravenous administration increased significantly by 84% or 241%, respectively, while there was no difference in the portal M-OH between control and ARF rats, suggesting that the elimination of M-OH was prolonged because of nephrotoxicity. Although the exsorption clearance of CsA from the blood circulation to the intestine after intravenous administration to ARF rats decreased significantly as compared to the control; and basolateral-to-apical transport of CsA through Caco-2 monolayers was significantly retarded in the presence of uremic toxins, there was no significant change in the total body clearance of CsA between ARF and control rats. Moreover, there were no effects of uremic toxins on the protein binding of CsA in plasma. These observations suggest that hepatic or intestinal CYP3A and P-glycoproteine (P-gp) are not likely to be concerned with lowering the oral bioavailability of CsA, and that bile function under the ARF condition induced by gentamicin is responsible for a marked decrease in the fraction absorbed of CsA in the small intestine.
Vancomycin clearance decreased with decreasing cardiac function (LVEF) and decreasing CLcr. This finding suggests that vancomycin clearance is affected by cardiac function and would be predicted not only CLcr but also by LVEF.
Losartan, a selective angiotensin receptor antagonist, is mainly metabolized by CYP2C9 to an active carboxylic acid, E3174, which is pharmacologically more potent inhibitor than the parent compound. We evaluated the effect of bucolome, a CYP2C9 inhibitor, on the pharmacokinetics of losartan and E3174, which were measured by high performance liquid chromatography in human volunteers and rats. A randomized crossover design study with two phases was done in the volunteer study. In the first phase, the volunteers received losartan 25 mg alone orally (LOS group), and, in the second phase, losartan 25 mg was given after repeated oral administration of 300 mg bucolome for 7 days (LOS+BUC group). In the LOS group, the maximum concentration (C(max)) and area under the concentration curve (AUC) of losartan were significantly higher than in the LOS+BUC group. On the other hand, in the LOS+BUC group, the C(max) and AUC of E3174 were significantly lower than in the LOS group. In the rat study, male Wistar ST rats were used. In the first phase, the rats orally received losartan 10 mg/kg alone or after bucolome was given repeatedly at a dose of 20, 50, or 200 mg/kg for 7 days. In the second phase for steady state, the rats were given losartan 10 mg/kg for 14 days (group A) or losartan 10 mg/kg and bucolome 50 mg/kg for 14 days (Group B). Bucolome at doses 50 and 200 mg/kg significantly increased the AUC losartan and significantly decreased the AUC of 3174. At the steady state, there were no significant differences in AUC of losartan between Group A and B, but the C(max) and AUC of E3174 were significantly lower in Group B than Group A.
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