Enhancement of exposure and reduction of elimination for paeoniflorin or albiflorin via co-administration with total peony glucosides and hypoxic pharmacokinetics comparison

OBJECTIVE Paeoniflorin(PF) and albiflorin(AF) are the major active components of total peony glucosides(TPG) from Paeonia lactiflora Pal,which have many biological activities such as anti-inflammatory,antioxidation and anti-hypertension effects.The drug-drug pharmacokinetic interaction among PF,AF and TPG,the pharmacokinetic comparisons of AF between hypoxia and normoxia,the transport of AF cross the blood-brain barrier cell model and the transport of AF/PF/TPG cross Caco-2 cell model were investigated.METHODS A highly sensitive and rapid UPLC-MS method with multiplereaction monitoring(MRM) scanning via electrospray ionization(ESI) source operating both in the positive and negative ionization mode was successfully developed and validated for simultaneous quantitation of PF and AF in rat plasma after an oral administration of PF,AF and TPG.RESULTS The validated and developed UPLC-MS/MS method was successfully applied to simultaneously determine the AF and PF concentration in rat plasma and investigate pharmacokinetic interactions after a single intragastrical ad.ministration of PF,AF,co-administration of PF with AF and TPG,respectively.The elimination of both PF co-administered with AF and PF in TPG were slower than those for PF alone and the distribution in the tissues was wider.The combination of PF with AF or TPG could significantly increase the values of the AUC,MRT and t1/2 of the drug PF,and reduce the values of CL of PF.From a comparison of the main pharmacokinetic parameters among AF alone,AF combined with PF and AF in TPG,the values of the MRT and t1/2 of AF in TPG were greater than that of AF alone,and there were statistically signifi.cant differences in these parameters(P<0.05,P<0.01).It was also noticed that AUC and Cmax of PF in hypoxia rats were significantly decreased compared with that of normaxia rats,suggesting that there was a decreased exposure of PF in rats under hypoxia.The multiple active components in TPG may lead to DDIs between some P-gp substrates.CONCLUSION The clinical performance of total peony glucosides would be better than that of single constitute.The outcomes of the study are expected to serve as a basis for development of clinical guidelines on total peony glucosides usage.

OBJECTIVE Paeoniflorin （PF） and albiflorin （AF） are the major active components of total peony glucosides （TPG） from Paeonia lactiflora Pal, which have many biological activities such as anti-inflammatory, antioxidation and anti-hypertension effects. The drug-drug pharmacokinetic interaction among PF, AF and TPG, the pharmacokinetic comparisons of AF between hypoxia and normoxia, the transport of AF cross the blood-brain barrier cell model and the transport of AF/PF/TPG cross Caco-2 cell model were investigated. METHODS A highly sensitive and rapid UPLC-MS method with multiple- reaction monitoring （MRM） scanning via electrospray ionization （ESI） source operating both in the positive and negative ionization mode was successfully developed and validated for simultaneous quantitation of PF and AF in rat plasma after an oral administration of PF, AF and TPG. RESULTS The validated and developed UPLC-MS/MS method was successfully applied to simultaneously determine the AF and PF concentration in rat plasma and investigate pharmacokinetic interactions after a single intragastrical administration of PF, AF, co-administration of PF with AF and TPG, respectively. The elimination of both PF co-administered with AF and PF in TPG were slower than those for PF alone and the distribution in the tissues was wider. The combination of PF with AF or TPG could significantly increase the values of the AUC, MRT and t^2 of the drug PF, and reduce the values of CL of PF. From a comparison of the main pharmacokinetic parameters among AF alone, AF combined with PF and AF in TPG, the values of the MRT and t1/2 of AF in TPG were greater than that of AF alone, and there were statistically significant differences in these parameters （P〈0.05, P〈0.01）. It was also noticed that AUC and Cmax of PF in hypoxia rats were significantly decreased compared with that of normaxia rats, suggesting that there was a decreased exposure of PF in rats under hypoxia. The multiple active components in TPG may lead to DDIs between some P-gp substrates. CONCLUSION The clinical performance of total peony glucosides would be better than that of single constitute. The outcomes of the study are expected to serve as a basis for development of clinical guidelines on total peony glucosides usage.