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The study was designed to explore the drug-drug interactions mechanisms mediated by OATP1B1 between traditional Chinese medicine Danshensu and rosuvastatin. First, the changes of rosuvastatin pharmacokinetics were investigated in presence of Danshensu in rats. Then, the primary rat hepatocytes model was established to explore the effects of Danshensu on the uptake of rosuvastatin by hepatocytes. Finally, HEK293T cells with overexpression of OATP1B1*a and OATP1B1*5 were established using a lentiviral delivery system to explore the effects of Danshensu on the uptake of rosuvastatin. Rosuvastatin pharmacokinetic parameters of C(max0, AUCO(0-t), AUC(0-∞) were increased about 123%, 194% and 195%, by Danshensu in rats, while the CL z/F value was decreased by 60%. Uptake of rosuvastatin in the primary rat hepatocytes was decreased by 3.13%, 41.15% and 74.62%, respectively in the presence of 20, 40 and 80 μmol x L(-1) Danshensu. The IC50 parameters was (53.04 ± 2.43) μmol x L(-1). The inhibitory effect of Danshensu on OATP1B1 mediated transport of rosuvastatin was related to the OATP1B1 gene type. In OATP1B1*5-HEK293T mutant cells, transport of rosuvastatin were reduced by (39.11 ± 4.94)% and (63.61 ± 3.94)%, respectively, by Danshensu at 1 and 10 μmol x L(-1). While transport of rosuvastatin was reduced by (8.22 ± 2.40)% and (11.56 ± 3.04)% and in OATP1B1*1a cells, respectively. Danshensu significantly altered the pharmacokinetics of rosuvastatin in rats, which was related to competitive inhibition of transport by OATPJBI. Danshensu exhibited a significant activity in the inhibition of rosuvastatin transport by OATP1B1*5-HEK293T, but not by OATP1B1*1a, suggesting a dependence on OATP1B1 sequence.
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Cytochrome P450 enzymes are composed of many isozymes and involved in the biotransformation of both exogenous and endogenous substances. A growing number of studies have found that the P450 enzymes do not always follow the classical Michaelis-Menten kinetics, but show atypical kinetic behavior, which is also the current research hotspot. In this paper, the category and mechanisms of atypical kinetics of the P450 enzyme were reviewed, providing theoretical basis for the research of enzyme kinetics.
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This study is to investigate the transportation of scutellarin in cell and live models and study on mechanism of absorption and transport of scutellarin in mouse liver. The concentration of scutellarin in plasma and liver from control and pretreated groups was determined by high performance liquid chromatography. The uptake of scutellarin was examined in control hepatocytes group, induced hepatocytes group and induced hepatocytes plus pravastatin group. Pravastatin can affect the pharmacokinetics of scutellarin in mouse: CL is decreased while AUC is increased. The scutellarin absorption of hepatocyte induced group was higher than that of control group, but was decreased in the group with pravastatin added. The research showed that there was potential drug interaction between pravastatin and scutellarin. The drugs may compete for oatp2 mediated transport pathway consisted in the uptake of scutellarin in liver.
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Scutellarin is the major effective ingredient of breviscapine, which is widely used in the treatment of cardiovascular diseases and has a remarkable achievement. In recent years, more and more reseaches had focused on the pharmacokinetics of scutellarin and scutellarein. The article summarized the studies on pharmacokinetics of scutellarin and scutellarein have been performed by domestic and oversea scholars.
Subject(s)
Animals , Humans , Apigenin , Pharmacokinetics , Flavonoids , Chemistry , Glucuronates , PharmacokineticsABSTRACT
Objective To explore the pharmacokinetic characteristics of telmisartan in Chinese healthy volunteers. Methods 9 Chinese male healthy volunteers were divided into receiving orally a single dose of 40, 80, 120 mg telmisartan tablets respectively, in latin square design study. After administration of telmisartan tablets, the plasma concentration was determined by HPLC with fluorescent detection. The pharmacokinetic parameters were analyzed by 3P97 program. Results It was found that plasma levels increased after orally increased dosages of telmisartan in the healthy volunteers in a nor-dose-dependent manner. The pharmacokinetic parameters were calculated the follows: AUC 0-96 of three different dosages (40, 80,120 mg) were (895.03?364.53), ( 3 030.34? 1 454.80) and ( 13 570.44? 3 551.54) ?g?h -1?L -1; and C max were (60.71?28.10), (214.05?74.14) and (978.32?234.89) ?g?L -1. There were significant differences in AUC 0-t/dose, C max/dose between the groups (P
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AIM: To study the linear relationship between pharmacokinetic parameters and doses about potassium clavulanic acid (CAV) and amoxicillin (AMX). METHODS: 15 healthy male volunteers were randomly divided into 5 dose groups. The plasma concentration of CAV and AMX was determined by high performance liquid chromatography (HPLC) method. The pharmacokinetic parameters obtained with 3p97 soft were regressed to corresponding dose. RESULTS: The regression equations of AUC and c max to dose about CAV were Y= 2.0895 X+ 0.4438 (r= 0.9915 ) and Y= 0.9397 X+ 0.1796 (r= 0.9922 ), respectively. The regression equations of AUC and c max to dose about AMX were Y= 4.8795 X+ 2.4794 (r= 0.9988 ) and Y= 1.7276 X+ 1.4832 (r= 0.9935 ), respectively. CONCLUSION: There is good linear relationship between pharmacokinetic parameters and doses about CAV and AMX.
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Aim To study the pharmacokinetics and bioequivalence of nimesulide dispersible tablet and its normal tablet. Methods 20 healthy volunteers were treated with a single oral dose of domestic nimesulide dispersible tablet or normal tablet (control) in a randomized crossover study and the plasma drug concentration was determined by HPLC. Results The plasma concentration time curve was fitted to the one compartment model. The pharmacokinetic parameters obtained were: c max ( 3.91 ? 0.74) ?g ?ml -1 , t (1/2)? ( 3.40 ? 0.78) h , t max ( 3.15 ? 0.67) h , AUC 0～24 ( 31.92 ? 6.36) ?g ?ml?h -1 , there was no significant difference between the active and control groups. The relative bioavailability obtained was ( 96.43 ? 8.41 ) %. Conclusion The pharmacokinetic profile for the 2 tablets was similar so it may be concluded that they are bioequivalent.
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Object To observe the effect of tetrandrine (Tet) on the activity of cholinesterase (ChE) inhibited by organophosphate. Methods Activity of ChE in human blood was determined with Ellman's method and used as an index. Results The cumulative dose effect curves for inhibitory effect of dipterex on ChE were shifted to right and the maximal inhibitory effect of dipterex was obviously declined by Tet. The maximal reactivating rates of inhibited ChE were 20.5%, 38.3% and 80.2% when the concentrations of Tet were 0.4, 0.8 and 1.6 ?g/mL (P
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Object To study the reactivation of neferine (Nef) and pralidoxime chloride (2-PAM?Cl) on mice brain cholinestrase (ChE) inhibited by organophosphate. Methods Micro-DTNB method was used to determine the ChE activity of mice brain inhibited by DDVP in vitro and in vivo, then the inhibitory effect of DDVP (0.001-0.03 mg/L) on mice brain ChE in vitro was observed. The reactivative effect of Nef and 2-PAM?Cl on brain ChE of poisoned mice with DDVP in vivo and in vitro was compared. Results In vitro, the inhibitory effect of DDVP at different concentrations on mice brain ChE showed a concentration-effect relationship. The IC_(50) was 0.003 mg/L. The reactivative effect of Nef (2.4, 4.8 mg/L) and 2-PAM?Cl (5, 12.5 mg/L) on brain ChE inhibited by DDVP (0.02 mg/L) enhanced with increasing their concentrations. In vivo, after 30 min of treated with DDVP (10 mg/L, sc), the mice were given (ip) with Nef (15, 30 mg/kg) or 2-PAM?Cl (25, 50 mg/kg), respectively. The ChE activity rate in these two treated groups were (41.6?10.9) %, (56.5?12.4) % and (24.1?14.3) %, (28.4?11.9) %, respectively. The difference between poisoned group (sc DDVP) and Nef treated group was significant (P0.05). Conclusion The results suggest that Nef have a more remarkable reactivative effect on inhibited brain ChE in vitro and in vivo than 2-PAM?Cl. This may be contributed to that Nef can penetrate the blood-brain barrier.
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Aim An HPLC method was established for the study on pharmacokinetics and bioequivalence of oxaprozin enteric tablet in healthy volunteers.Methods The oxaprozin in plasma was determined using HPLC method following a single oral dose of 400 mg of oxaprozin given respectively to 18 healthy male volunteers in an open randomized crossover design.The pharmacokinetic parameters and relative bioavailability were calculated to evaluate the bioequivalence of 2 preparations.Results AUC_(0-240 h) of oxaprozin tested tablet and reference tablet were(2852.86?871.00)and (2992.84?854.02)?g?L~(-1)?h,C_(max) were(33.48?11.36)and (32.70?7.30)?g?L~(-1),T_(max) were(12.1?5.7)and(13.8?5.8)h,T_(1[]2ke) were(57.11?8.51)and(60.98?7.97)h,respectively.These main pharmacokinetic parameters obtained showed no statistically significant difference between the 2 products.Conclusion The method is simple and sensitive.Both preparations are bioequivalent.
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AIM To investigate the reativative and protective effect of Neferine (Nef) on the poisoning mice of cholinesterase (ChE) with dichlorves (DDVP) or dipterex (Dip) of LD 100 . METHODS The mice were randomly divided into poisoning group with DDVP or Dip and Nef, Atropine and Pyraloxime methylchloride (PAM Cl) treatment group. Activity of mice blood ChE was determined with Ellmaris method, and acute toxicity experiment was used to determine the protective effect. RESULTS ① Nef (15 mg?kg -1 , ip) exhibited a definite protective effect on poisoning mice, and the mortality of the animals treated with Nef was significantly lower than that of the control group with normal saline ( P 0 05). But Nef and atropine group was significantly lower than that of thePAM Cl group ( P
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Aim The metabolic character of neferine(Nef) in rat liver microsomes was studied in vitro to identify which isoforms of cytochrome P450 were responsible for Nef metabolism in rats.Methods ① Wistar rats were untreated or treated with various inducers including dexamethasone(DEX,50 mg?kg~(-1),ig?4 d),phenobarbital(PB,75 mg?kg~(-1),ip?3 d) and ?-naphthoflavone(?-NF,80 mg?kg~(-1),ip?3 d).Liver microsomes were obtained from these rats and incubated with Nef in the presence of reduced form of nicotinamide adenine dinucleotide phosphate.A HPLC-UV method was developed to determine Nef and its metabolites.② The enzyme kinetics of the metabolism of Nef was investigated in rat liver microsomes.③ Troleandomycin,a CYP3A selective inhibitor,was used to study its inhibitory effect on the metabolism of Nef in vitro.Results ① The metabolism of Nef in rat liver microsomes showed the characteristic of enzymekinetics.② The correlation between peak area of a metabolite and original concentration of Nef in rat liver microsomes solution was significant(r=0.993).③ The disappearing rate of Nef in the incubation solutions of the rats liver microsomes,which treated with DEX or PB,were markedly quicker than that of control group(P0.05).The average disappearing rates of Nef in rat liver microsomes after incubation with different inducers were as follows: DEX,80.6%?9.5%;PB,61.5%?6.7%;?-NF,20.7%?1.5%;Control,19.9%?1.6%.④ Troleandomycin could significantly inhibit the metabolism of Nef in rat liver microsomes.Conclusion Our results suggest that both CYP3A and CYP2B are involved in Nef metabolism in rats liver microsomes,and CYP3A probably play a major role.
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0.05).Conclusion The pharmacokinetic characteristic of sertraline in Chinese healthy volunteers(in 50~150mg process) were fitted with linear kinetic model.