Xiaoquan Liu

Effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism

1. The objective of this study was to investigate the effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism. 2. After oral administration of diammonium glycyrrhizinate (50 mg kg−1), the peak plasma concentration (Cmax), area under the plasma concentration–time curve from zero to time τ (AUC0–τ), and absolute bioavailability of aconitine (0.2 mg kg−1) significantly increased 1.64-, 1.63- and 1.85-fold, respectively, but there was no significant change in half life (t1/2) or clearance (CL). In the other two routes of administration via the tail vein and hepatic portal vein, diammonium glycyrrhizinate (15 mg kg−1) did not affect any of the pharmacokinetic parameters of aconitine (0.02 mg kg−1). Thus, diammonium glycyrrhizinate can enhance the absorption of aconitine, leading to higher oral bioavailability and plasma levels, but it does not influence its elimination. 3. Moreover, an in vitro everted gut sac model and Ussing chamber model were used to investigate the potential mechanism. Results from bidirectional transport and inhibition studies demonstrated that P-glycoprotein was the main efflux transporter involved in the absorption of aconitine in rats. The absorption enhancement effect of diammonium glycyrrhizinate should be mainly attributed to inhibiting the activity of P-glycoprotein rather than to the influence on the paracellular or transcellular transport.

Metabolism and metabolic inhibition of gambogic acid in rat liver microsomes

AbstractAim:To study the metabolism of gambogic acid (GA) and the effects of selective cytochrome P-450 (CYP450) inhibitors on the metabolism of GA in rat liver microsomes in vitro.Methods:Rat liver microsomes were used to perform metabolism studies. Various selective CYP450 inhibitors were used to investigate their effects on the metabolism of GA and the principal CYP450 isoform involved in the formation of major metabolite M1 in rat liver microsomes. Types of inhibition in an enzyme kinetics model were used to model the interaction.Results:GA was rapidly metabolized to two phase I metabolites, M1 and M2, in rat liver microsomes. M1 and M2 were tentatively presumed to be the hydration metabolite and epoxide metabolite of GA, respectively. α-Naphthoflavone uncompetitively inhibited the formation of M1 while ketoconazole, sulfaphenazole, diethyl dithiocarbamate and quinidine had little or no inhibitory effects on the formation of M1.Conclusion:GA is rapidly metabolized in rat liver microsomes and M1 is crucial for the elimination of GA. Cytochrome P-450 1A2 is the major rat CYP involved in the metabolism of GA.

Pharmacokinetic interactions induced by content variation of major water-soluble components of Danshen preparation in rats

AbstractAim:To investigate the pharmacokinetic interactions induced by content variation of the main water-soluble components of Danshen injection in rats.Methods:Intravenous Danshen injection (control) or Danshen injection with danshensu (DSS), protocatechuic aldehyde (PAL), salvianolic acid A (Sal A) or salvianolic acid B (Sal B) were administered to female Sprague Dawley rats . Plasma concentrations of DSS, Sal A, PAL and its oxidative metabolite protocatechuic acid (PA) were analyzed simultaneously with LC-MS/MS; concentrations of Sal B were determined by the LC-MS method. Non-compartmental pharmacokinetic parameters were calculated and compared for identifying the pharmacokinetic interactions among these components.Results:Compared with the control group, the DSS, Sal A, and Sal B groups had significant increases in AUC0-∞ in response to elevated concentrations of PAL (by 78.1%, 51.0%, and 82.9%, respectively), while the clearances (CL) were markedly reduced (by 42.5%, 32.9%, and 46.8%, respectively). Similarly, Sal A increased the AUC0–∞ of DSS and Sal B (26.7% and 82.4%, respectively) and substantially decreased their clearances (21.4% and 45.6%, respectively). In addition, the pharmacokinetics of DSS and Sal B were significantly affected by the content variation of the other major components; the AUC0-∞ increased by 45.1% and 52.1%, respectively, the CL dropped by 29.6% and 27.1%, respectively, and the T1/2 was decreased by 22.0% and 19.6%, respectively.Conclusion:Complex, extensive pharmacokinetic interactions were observed among the major water-soluble constituents in the Danshen injection. The content variation of PAL had the most significant effect on the pharmacokinetic behaviors of other major constituents. Furthermore, the pharmacokinetics of DSS and Sal B were the most susceptible to the content change of other components.

Pharmacokinetics, tissue distribution and excretion of gambogic acid in rats

SummaryThe plasma pharmacokinetics, excretion, and tissue distribution of gambogic acid (GA), a novel anti-tumor drug, were investigated after intravenous (i.v.) bolus administration in rats. Plasma profiles were obtained after i.v. administration of GA at the doses of 1, 2 and 4 mg/kg. The elimination half-life (t1/2) values for GA were estimated to be 14.9, 15.7 and 16.1 min, while the mean area under concentration-time curve (AUCt) values were 54.2, 96.1 and 182.4 μg·min/ml, respectively. GA was mainly excreted into the bile (36.5% over 16 h). The cumulative sum of fecal excretion within 48 h was 1.26% of the i.v. administered dose. No GA was detected in the urine after i.v. administration. GA had a limited tissue distribution, with the highest concentrations being found in the liver. GA reached its maximal concentration in all tissues at 5 min post-dose. In conclusion, the present observations indicated that GA was rapidly eliminated from the blood and transferred to the tissues. Moreover, the majority of GA appeared to be excreted into the bile within 16 h of i.v. administration.

Metabolism of protocatechuic acid influences fatty acid oxidation in rat heart: New anti-angina mechanism implication

Protocatechuic acid (PA), a structurally typical phenolic acid in danshen, shows anti-angina efficacy. But until now, besides scavenging of oxygen free radicals, the understanding of its anti-angina mechanism has been limited. In our study, based on a novel metabolic route of PA identified in rat heart and its influence on fatty acid oxidation (FAO), we proposed a new mechanism for its anti-angina. In detail, three metabolites, catechol methylated metabolite, acyl-coenzyme (CoA) thioester and glycine conjugation, were identified in rat heart. A novel metabolic pathway was confirmed based on several metabolic systems incubated with heart mitochondria, cytosol, microsomes and homogenate. Results indicated that PA was firstly methylated in microsomes and cytosol, which was regarded as the prerequisite step for further metabolism and could be inhibited by tolcapone, and then the resulting methylated metabolite (vanillic acid) diffused into mitochondria where it was converted into acyl-CoA thioester, in similar with FAO. In addition, part of the acyl-CoA thioester was transformed into glycine conjugation, a step also localized within mitochondria. Furthermore, based on isolated rat heart perfusion, it was found that PA markedly decreased FAO, which was shown by higher residual fatty acid level in perfusate (p<0.05) and lower acy-CoA/CoA ratio in heart (p<0.05). The FAO inhibiting effect of PA could be largely reversed by its methylation inhibitor tolcapone, indicating the effect was closely related with the identified metabolic pathway of PA in heart. The decrease of FAO may switch heart energy substrate preference from fatty acid to glucose, which is beneficial for ischemia heart.

Using neural networks to determine the contribution of danshensu to its multiple cardiovascular activities in acute myocardial infarction rats

ETHNOPHARMACOLOGICAL RELEVANCE Danshensu is an active water-soluble component from Salvia Miltiorrhiza, which has been demonstrated holding multiple mechanisms for the regulation of cardiovascular system. However, the relative contribution of danshensu to its multiple cardiovascular activities remains largely unknown. AIM OF THE STUDY To develop an artificial neural network (NN) model simultaneously characterizing danshensu pharmacokinetics and multiple cardiovascular activities in acute myocardial infarction (AMI) rats. The relationship between danshensu pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated using contribution values. MATERIALS AND METHODS Danshensu was intraperitoneally injected at a single dose of 20mg/kg to AMI rats induced by coronary artery ligation. Plasma levels of danshensu, cardiac troponin T (cTnT), total homocysteine (Hcy) and reduced glutathione (GSH) were quantified. A back-propagation NN model was developed to characterize the PK and PD profiles of danshensu, in which the input variables contained time, area under plasma concentration-time curve (AUC) of danshensu and rat weights (covariate). Relative contribution of input variable to the output neurons was evaluated using neuron connection weights according to Garsons algorithm. The kinetics of contribution values was also compared and was validated using bootstrap resampling method. RESULTS Danshensu exerted significant cTnT-lowering, Hcy- and GSH-elevating effect, and these marker profiles were well captured by the trained NN model. The calculation of relative contributions revealed that the effect of danshensu on the PD marker could be ranked as cTnT>GSH>Hcy, while the effect of AMI disease on the PD marker could be ranked in the following order: cTnT>Hcy>GSH. The activity of transsulfuration pathway was quite obvious under the AMI state. CONCLUSION NN is a powerful tool linking PK and PD profiles of danshensu with multiple cardioprotective mechanisms, it provides a simple method for identifying and ranking relative contribution to the multiple therapeutic effects of the drug.

Pharmacokinetic-pharmacodynamic modeling of telmisartan using an indirect response model in spontaneously hypertensive rats

AbstractAim:To investigate the pharmacokinetic (PK) and the pharmacodynamic (PD) properties of telmisartan in spontaneously hypertensive (SH) rats using an indirect response and effect-compartment link models, and compare two PK-PD models fitting quality.Methods:The SH rats received a single oral dose of 2, 4, and 8 mg/kg of telmisartan. The plasma concentrations of telmisartan were determined by the liquid chromatography-mass spectrum method. The mean arterial blood pressure was measured to characterize the pharmacodynamics of telmisartan by tail-cuff manometry. The relationship for the telmisartan concentration-hypotensive effect in the SH rats was characterized using an indirect response model.Results:The PK parameters showed dose proportionality, with a long terminal half-life of 16 h, a clearance of 0.15 L·kg−1·h−1, and a volume of distribution of 5.36 L·kg−1 in the study. For the indirect response PD model, the estimated Kin were 36.6, 34.1, and 32.8 %·h−1, Kout were 36.7, 34.6, and 31.9 h−1; the IC50 values were 86.2, 95.8, and 91.1 ng·mL−1; and the area under the effect curve (AUEC) were 762.8, 1490.5, and 2086.2 mmHg·h at three doses, respectively. For the effect-compartment model, the Keo were 29.4, 33.8, and 28.7 h−1; the IC50 values were 78.2, 85.7, and 80.9 ng·mL−1, and the AUEC were 781.5, 1602.8, and 2215.7 mmHg-hat three doses, respectively.Conclusion:According to Akaikes information criterion values, the proposed indirect response model provided a more appropriate and good-fitting PK/PD characterization of telmisartan than the effect-compartment link model in SH rats.

CYP3A4 mediated in vitro metabolism of vinflunine in human liver microsomes

AIM To study the metabolism of vinflunine and the effects of selective cytochrome P-450 (CYP450) inhibitors on the metabolism of vinflunine in human liver microsomes. METHODS Individual selective CYP450 inhibitors were used to investigate their effects on the metabolism of vinflunine and the principal CYP450 isoform involved in the formation of metabolites M(1) and M(2) in human liver microsomes. RESULTS Vinflunine was rapidly metabolized to 2 metabolites: M(1) and M(2) in human liver microsomes. M(1) and M(2) were tentatively presumed to be the N-oxide metabolite or hydroxylated metabolite and epoxide metabolite of vinflunine, respectively. Ketoconazole uncompetitively inhibited the formation of M(1), and competitively inhibited the formation of M(2), while alpha-naphthoflavone, sulfaphenazole, diethyl dithiocarbamate, tranylcypromine and quinidine had little or no inhibitory effect on the formation of M(1) and M(2). CONCLUSION Vinflunine is rapidly metabolized in human liver microsomes, and CYP3A4 is the major human CYP450 involved in the metabolism of vinflunine.

A novel metabolic balance model for describing the metabolic disruption of and interactions between cardiovascular-related markers during acute myocardial infarction

OBJECTIVE After acute myocardial infarction (AMI), an integral evaluation of risk using multimarker approach and the understanding of the pathophysiological processes involved have recently received much attention. This study aimed to develop a model to integrally evaluate the metabolic disruption of cardiovascular-related markers and unveil their interactions after AMI. METHODS AMI was induced in rats by coronary artery ligation. Several cardiovascular-related markers in plasma and the heart were determined during AMI. A metabolic balance model was developed using matrix equations to assess the metabolic disturbance of, and interactions between, these markers. RESULTS Metabolic balance maps intuitively depicted the metabolic disruption of cardiovascular-related markers after AMI. The deviation and magnitude of the disruption were quantitatively and integrally described by φ and k (the dynamic parameter of metabolic balance disruption), respectively. The metabolic balance was disturbed in both the circulatory system and the heart post-AMI. All of the measured markers appeared to be interactional. Among these markers, kidney function and dimethylarginine dimethylaminohydrolase (DDAH) activity in the heart showed a potent effect on the other markers, whereas asymmetric dimethylarginine (ADMA) levels in plasma and adenosine triphosphate (ATP) contents in the heart were susceptible to the effects of the other markers. CONCLUSION A metabolic balance model was developed to integrally evaluate the disruption of cardiovascular-related markers after AMI, which proposes a new method for evaluating the disease state post-AMI using a multimarker approach. The unveiled interactions between these cardiovascular-related markers are helpful in understanding the pathophysiological processes.

Effects of salvianolic acid A on plasma and tissue dimethylarginine levels in a rat model of myocardial infarction.

Abstract: This study aimed to investigate the effects of salvianolic acid A (Sal A) on the time course of plasma and tissue dimethylarginine levels after myocardial infarction (MI) induced by left coronary artery ligation. The rats were assigned to 4 groups: Sham, MI, and MI treated with Sal A (1 or 5 mg/kg). The results showed that plasma symmetric dimethylarginine and asymmetric dimethylarginine (ADMA) levels separately reached the peak at the first and second day after MI. Dimethylarginine dimethylaminohydrolase (DDAH) activity in the heart was remarkably inhibited on the initial 2 days. Sal A restored DDAH activity in the heart and decreased the elevated plasma ADMA levels. ADMA concentrations in the heart and liver were significantly increased after MI, which could also be reduced by Sal A. In addition, Sal A showed regulating effects on symmetric dimethylarginine levels in the liver and also in the ischemic zone of heart. In conclusion, the variations of dimethylarginines in plasma and tissues were induced by the inhibition of DDAH activity and their leakage in the infarct zone after MI. Sal A exerted beneficial effects in MI by decreasing plasma and tissue dimethylarginine levels via restoring DDAH activity.