Myocardial pharmacokinetics of ebastine, a substrate for cytochrome P450 2J, in rat isolated heart

BACKGROUND AND PURPOSE

It is well established that cytochrome P450 2J (CYP2J) enzymes are expressed preferentially in the heart, and that ebastine is a substrate for CYP2J, but it is not known whether ebastine is metabolized in myocardium. Therefore, we investigated its pharmacokinetics in the rat isolated perfused heart.

EXPERIMENTAL APPROACH

Rat isolated hearts were perfused in the recirculating mode with ebastine for 130 min. The concentrations of ebastine and its metabolites, hydroxyebastine and carebastine, were measured using liquid chromatography with a tandem mass spectrometry. The data were analysed by a compartmental model. The time course of negative inotropic response was linked to ebastine concentration to determine the concentration–effect relationship.

KEY RESULTS

Ebastine was metabolized to an intermediate compound, hydroxyebastine, which was subsequently further metabolized to carebastine. No desalkylebastine was found. The kinetics of the sequential metabolism of ebastine was well described by the compartmental model. The EC₅₀ of the negative inotropic effect of ebastine in rat isolated heart was much higher than free plasma concentrations in humans after clinical doses.

CONCLUSIONS AND IMPLICATIONS

The kinetics of ebastine conversion to carebastine via hydroxyebastine resembled that observed in human liver microsomes. The results may be of interest for functional characterization of CYP2J activity in rat heart.     

Endothelium-independent vasorelaxation by ticlopidine and clopidogrel in rat caudal artery

Objectives Thienopyridines are prodrugs currently used as anti‐aggregating agents. The aim of this study was to determine if these compounds might have vascular activity independent of hepatic bioactivation. Methods The direct activity of thienopyridines was studied in rat caudal arterial rings and aortic smooth muscle cells in culture. Key findings Both compounds (0.01 µm –100 µm ) showed a concentration‐dependent vasorelaxation in arterial tissues precontracted with phenylephrine, 5‐hydroxytryptamine and KCl. The relaxation induced by 100 µm ticlopidine and clopidogrel was greater than 80%. The relaxation by ticlopidine was compared with the activity of acetylcholine. These two agents showed similar potency, although ticlopidine was slightly more active. Pretreatment with the nitric oxide synthase inhibitor L‐NAME inhibited the relaxation by acetylcholine but not that by ticlopidine. To further study vasorelaxation by ticlopidine, other pharmacological inhibitors including propranolol, nifedipine and suramin were used. These compounds lacked inhibitory effects on the vasorelaxation by ticlopidine. In vascular smooth muscle cells, 1 µm ticlopidine induced a decrease in cell proliferation, while incubation with both ticlopidine and ADP or 2‐methioADP led to an additive effect. Conclusions The data suggest that ticlopidine and clopidogrel cause relaxation of arterial tissues and influence vascular smooth muscle cell proliferation directly without hepatic biotransformation. Furthermore, the arterial relaxation induced in vitro by thienopyridines is endothelium independent, and β‐adrenergic and P2 receptors are not involved.     

Application of pharmacokinetic/pharmacodynamic and stochastic modelling to 6-mercaptopurine micronucleus induction in mouse bone marrow erythrocytes

This study investigates the kinetics of bone marrow micronucleated polychromatic erythrocytes and some mechanistic aspects of micronuclei induction using mathematical models. Female mice were administered a single intraperitoneal injection of the purine antagonist 6-mercaptopurine at 50 mg kg(-1). The time course evolution of the drug concentrations in the plasma and the micronucleated polychromatic erythrocyte kinetic rate in bone marrow were observed. Two mathematical models were developed for this study. The first model was built from a simultaneous pharmacokinetic/pharmacodynamic approach, but was invalidated after comparing its predictions to experimental data. The second model was a stochastic model based on some biological hypotheses involved in micronuclei induction. This model predicted a wavy kinetic rate of micronucleated polychromatic erythrocytes that was confirmed by a second data set obtained from a specifically built experimental design. The biological hypotheses were then discussed. It turned out from this work that mathematical modelling could be used as a tool to explore the cellular mechanisms of toxicity of the compound: for instance, the assumptions that 6-mercaptopurine induced micronuclei mainly in cells entering the S phase, and not only during the last cell cycle but during one of the earlier cycles preceding the extrusion of the main nucleus, were confirmed. Moreover, the use of the stochastic model would help to schedule more accurately the bone marrow or blood harvesting times in the in vivo rodent micronucleus test.     

Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease

AIMS: The purpose of this study was to characterize the relationship between the degree of anticoagulation, assessed by APTT, and the plasma concentration of inogatran in healthy subjects and in patients with coronary artery disease. METHODS: Data from five phase I studies in 78 healthy males and two phase II multicentre studies in 948 patients of both sexes with unstable angina pectoris or non-Q-wave myocardial infarction were evaluated. A total of 3296 pairs of concentration-APTT samples were obtained before, during, and after intravenous infusions of inogatran. Mixed effects modelling was used for population pharmacodynamic analysis of the drug effect and for describing the variability in baseline APTT. RESULTS: The population mean baseline APTT was 29 s, but large variations between individuals (s.d. 3.6 s) were observed. The variability between studies (1.3 s) and centres (1.8 s) were of less importance, though statistically significant. APTT increased in a nonlinear manner with increasing inogatran concentration and the relationship was well described by a combined linear and Emax model. A significant part of the overall variability could be ascribed to the APTT reagent and equipment used at the different study centres. These method-dependent differences were compensated for by including the lower limit of the normal reference range as a covariate, affecting both baseline and Emax, in the model. For the typical healthy subject and patient, the method-corrected population mean parameters were: APTTbaseline 35 and 31 s, slope 8.0 and 5.8 s x l x micromol(-1), Emax 36 and 34 s, and EC50 0.54 and 0.72 micromol x l(-1), respectively. The model predicted plasma concentration needed to double the APTT from the baseline value was 1.25 and 1.45 micromol x l(-1) in the healthy volunteer and patient, respectively. CONCLUSIONS: The nonlinear relationship between APTT and inogatran concentration in plasma was well described by a combined linear and Emax model. Pooling of data was made possible by incorporating a centre-specific characteristic of the assay method in the model. Patients had lower baseline APTT and appeared to have less pronounced effect of inogatran than young healthy subjects.     

利多卡因对非体外循环冠状动脉旁路移植术患者血清炎性介质及氧自由基的影响

目的:研究利多卡因对非体外循环冠状动脉旁路移植术(OPCAB)患者血清炎性介质及氧自由基的影响。方法:30例择期行OPCAB的患者随机分为对照组(C组)和利多卡因组(L组),每组15例,两组麻醉方法相同。L组于麻醉诱导后静脉注射利多卡因2mg.kg-1,继以2mg.kg-1.h-1持续泵入至术毕;C组给予等量生理盐水。分别在麻醉诱导后手术前(T1)、乳内动脉游离结束肝素化后即刻(T2)、手术结束(T3)、术后24h(T4)采集中心静脉血,用ELISA法检测肿瘤坏死因子-α(TNF-α)、白细胞介素-8(IL-8);分光光度法检测超氧化物歧化酶(SOD)及丙二醛(MDA)。同时记录血流动力学指标及术后早期临床资料I、CU滞留时间、住院时间等。结果:①TNF-α、IL-8:与术前比较,两组TNF-α、IL-8术中及术后均明显升高(P<0.01),但L组升高幅度显著低于C组(P<0.01或0.05);②SOD、MDA:SOD两组组内各时点间和组间变化都不明显(P>0.05);MDA在L组各时点间变化无明显差异(P>0.05),C组MDA术后24h显著升高(P<0.01),组间比较差异显著(P<0.05);③L组患者...     

Pharmacokinetic/pharmacodynamic modelling of 2-acetyl-4(5)-tetrahydroxybutyl imidazole-induced peripheral lymphocyte sequestration through increasing lymphoid sphingosine 1-phosphate

1. 2-Acetyl-4(5)-tetrahydroxybutyl imidazole (THI) has been shown to reduce rodent peripheral blood lymphocytes through increasing lymphoid sphingosine 1-phosphate (S1P) by inhibiting S1P lyase. The objective of this study was to characterize the relationship between systemic THI exposure, splenic S1P concentrations, and lymphopenia in rats.

2. Following the oral administration of 10 and 100?mg kg^?1 THI to male rats, THI was rapidly absorbed and reached a plasma peak level at 1?h post-dosing. Splenic S1P increased and reached the peak level at 24?h. Blood lymphocyte count decreased as the splenic S1P level increased. THI plasma concentration was linked to splenic S1P concentration using an indirect model incorporated with a four-step signal transduction model. In turn, the S1P level was directly coupled with blood lymphocyte number. The integrated model simultaneously captured the splenic S1P and blood lymphocyte responses.

3. This pharmacokinetic–biomarker–pharmacodynamic model resolved the remarkable discrepancy between plasma THI concentration and the pharmacological response and quantitatively described the relationship of THI exposure, S1P, and lymphopenic response.

     

Interaction between udenafil and tamsulosin in rats: non-competitive inhibition of tamsulosin metabolism by udenafil via hepatic CYP3A1/2

Background and purpose:

Orthostatic hypotension has been observed when PDE 5 (cGMP-specific phosphodiesterase type 5) inhibitors are co-administered with α-adrenoceptor antagonists. Here we assessed the pharmacokinetic and haemodynamic interactions between udenafil and tamsulosin in rats, as both drugs are metabolized via rat hepatic cytochrome P450 3A1/2.

Experimental approach:

Interactions between the two drugs were evaluated in rats after simultaneous 1 or 15 min i.v. infusion or after p.o. administration of udenafil (30 mg·kg⁻¹) and/or tamsulosin (1 mg·kg⁻¹). In vitro metabolism of tamsulosin with udenafil was measured to obtain the inhibition constant (K_i) and [I]/K_i ratio of udenafil.

Key results:

The total area under the plasma concentration–time curve from time zero to time infinity (AUC)s (or AUC_0–4h) of tamsulosin were significantly greater after 15 min of i.v. infusion or after oral administration with udenafil, compared with tamsulosin alone. The hepatic first-pass metabolism of tamsulosin was inhibited by udenafil, and the inhibition in vitro was in a non-competitive mode. The arterial systolic blood pressure was significantly lower at 5, 10 and 60 min after oral co-administration of the drugs.

Conclusions and implications:

The significantly greater AUC of tamsulosin after i.v. and p.o. administration of both drugs may be attributable to non-competitive inhibition of cytochrome P450 3A1/2-mediated hepatic tamsulosin metabolism by udenafil. The inhibition was also observed in human liver S9 fractions, suggesting that a reassessment of the oral dosage of tamsulosin is necessary when udenafil and tamsulosin are co-administered to patients with benign prostatic hyperplasia.     

Involvement of sphingosine-1-phosphate and S1P1 in angiogenesis: Analyses using a new S1P1 antagonist of non-sphingosine-1-phosphate analog

Chemical lead 2 (CL2) is the first non-sphingosine-1-phosphate (Sph-1-P) analog type antagonist of endothelial differentiation gene-1 (Edg-1/S1P₁), which is a member of the Sph-1-P receptor family. CL2 inhibits [³H]Sph-1-P/S1P₁ binding and shows concentration-dependent inhibition activity against both intracellular cAMP concentration decrease and cell invasion induced by the Sph-1-P/S1P₁ pathway. It also inhibits normal tube formation in an angiogenesis culture model, indicating that CL2 has anti-angiogenesis activity. This compound improved the disease conditions in two angiogenic models in vivo. It significantly inhibited angiogenesis induced by vascular endothelial growth factor in a rabbit cornea model as well as the swelling of mouse feet in an anti-type II collagen antibody-induced arthritis model. These results indicate that the Sph-1-P/S1P₁ pathway would have an important role in disease-related angiogenesis, especially in the processes of migration/invasion and tube formation. In addition, CL2 would be a powerful tool for the pharmacological study of the mechanisms of the Sph-1-P/S1P₁ pathway in rheumatoid arthritis, diabetes retinopathy, and solid tumor growth processes.     

Effects of sphingosine-1-phosphate and sphingosylphosphorylcholine on intracellular Ca2+ and cell death in prostate cancer cell lines

The sphingolipid metabolites sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) can be involved in cellular growth and apoptosis, by both receptor-dependent and -independent mechanisms. We investigated the role of S1P and SPC in intracellular Ca2+ elevation, cell proliferation and cell death in DU 145 and PC3 hormone-refractory prostate cancer cell lines. S1P and SPC increased intracellular Ca2+ levels, most likely in a receptor-independent manner. Surprisingly, both S1P and SPC did not stimulate but rather reduced cell growth through induction of apoptosis. Therefore, antagonists targeted against S1P, SPC and their receptors do not appear to be promising new approaches in the treatment of hormone-refractory prostate cancer.     

Concentration-effect relationship of the positive chronotropic and hypokalaemic effects of fenoterol in healthy women of childbearing age

Objective: To analyse fenoterol-induced tachycardia and hypokalaemia, the most important and most frequent adverse effects of tocolytic therapy with β₂-adrenoceptor agonists in females of childbearing age. Methods: The study was performed as a double blind, randomised, placebo controlled, cross over trial. Seven healthy women aged 22–38 y, received intravenous infusions of fenoterol at 3 different rates within the therapeutic range for tocolysis (0.5,1.0, and 2.0 μg⋅min⁻¹) and placebo. The time courses of the plasma concentrations of fenoterol and potassium, and the heart rate were analysed with mixed effects pharmacokinetic-pharmacodynamic (PKPD) modeling using NONMEM. Results: The plasma concentration-time course followed a linear two compartment model. Fenoterol-induced tachycardia was described by a linear concentration-effect model with baseline. The estimated baseline and slope parameters were 78 beats⋅min⁻¹ and 0.032 beats⋅min⁻¹⋅μg⁻¹⋅l, respectively. Fenoterol-induced hypokalaemia could be described by a physiological indirect response model including feedback; the Estimated basal plasma potassium concentration was 3.93 mmol⋅l⁻¹ and the slope factor for the fenoterol-induced relative increase in the efflux of potassium from the extracellular space was 6.22^*10⁻⁴ ng⋅l⁻¹. Conclusion: The estimated population parameters permitted calculation of the expected time course of tachycardia and hypokalaemia in women after the initiation of tocolysis with fenoterol over the clinically relevant concentration range, and prediction of its variability. Based on simulation, our model predicted that a continous infusion of 2.0 μg⋅min⁻¹ (highest rate examined) would increase heart rate to 113 beats⋅min⁻¹ at steady state and lower the plasma potassium concentration to 2.77 mmol⋅l⁻¹ 1.5 h after beginning the infusion. Thereafter, the plasma potassium concentration would slowly return to normal. Received: 7 December 1995/Accepted in revised form: 29 April 1996     

ERK1/2通路参与ET_A和ET_B受体介导的离体肠系膜上动脉收缩研究

目的探讨细胞外信号调节激酶1/2(ERK1/2)信号转导通路在内皮素1(ET-1)的两个G蛋白偶联受体ET_A和ET_B介导的收缩机制。方法用大鼠肠系膜上动脉器官培养模型,以敏感的离体药理学实验方法记录培养前后血管平滑肌张力,实时定量的PCR测定培养前后受体mRNA表达水平的变化。结果S6c不引起新鲜的肠系膜上动脉收缩,培养后ETB受体mRNA表达水平上调,介导的收缩明显增强(P<005);而ETA受体介导的收缩功能和mRNA均变化不大。低浓度的SB386023(10-5mol·L-1)降低S6c引起的最大收缩(Emax从239%±26%降至89%±13%,P<001),而对ET1引起的最大收缩并无影响(Emax271%±19%vs251%±16%,P>005);高浓度的SB386023(10-4mol·L-1)明显抑制ETA受体介导的收缩。结论ET-1通过ET_A受体介导新鲜动脉的收缩;动脉培养后表达ET_B受体;ERK1/2信号转导通路对ET_B受体的作用强于ET_A受体。     

Mechanism-based pharmacokinetic/pharmacodynamic modeling of the effects of sitagliptin on DPP-4 activity,insulin and glucose in diabetic rats

Dipeptidyl peptidase-4 (DPP-4) inhibitors exert their antihyperglycemic effects through repressing inactivation of certain incretin hormones and thus increasing insulin secretion and controlling glucose level. In this study, the plasma concentrations of sitagliptin, a potent DPP-4 inhibitor, after a single oral dose of 300 mg/kg in streptozotocin-induced type 2 diabetic rats were determined by HPLC. A one-compartment pharmacokinetic (PK) model with first order absorption was developed to describe the PK profile of sitagliptin, and the drug concentrations at the doses given in the pharmacodynamic (PD) study were simulated accordingly. The dynamic changes in DPP-4 activity, insulin concentration and blood glucose level in diabetic rats at doses of 1, 5 and 10 mg/kg were measured, and a mechanism-based PK/PD model was established subsequently. In this model, the inhibitory effect of sitagliptin on DPP-4 activity was demonstrated using the Hill’s function with direct link, and the downstream increase in insulin secretion and inhibition of glucose production were characterized using indirect response (IDR) models. This model interpreted the mechanism of antihyperglycemic action of sitagliptin, and may be modified and applied to other species or other agents in this class.     

趋化因子MCP-1及MIP-2在实验性急性胰腺炎中的表达

目的 探讨单核细胞趋化蛋白-1(MCP-1)和巨噬细胞炎性蛋白-2(MIP-2)在重症急性胰腺炎(SAP)早期发病机制中的作用.方法 以4%牛磺胆酸钠逆行胆胰管注射制作大鼠SAP模型,检测血清淀粉酶,进行胰腺组织病理学评价,采用实时定量 RT-PCR方法检测各组胰腺组织中MCP-1 mRNA、MIP-2 mRNA表达的水平.结果 SAP大鼠血清淀粉酶与假手术组比较P＜0.01,随时间延长,逐步升高.胰腺组织中MCP-1 mRNA、MIP-2 mRNA表达高于假手术组,且表达水平与胰腺病理严重程度正相关P分别＜0.05,＜0.01.结论 MCP-1和MIP-2在SAP早期发病机制中可能发挥重要作用.     

Pharmacokinetic interaction between DA-8159, a new erectogenic, and metformin in rats: competitive inhibition of metabolism via hepatic CYP3A1/2

BACKGROUND AND PURPOSE: Erectile dysfunction is highly prevalent in diabetic patients and PDE V inhibitors are effective and safe for the treatment of erectile dysfunction in men with diabetes. Therefore, in this study we investigated whether a pharmacokinetic interaction occurs between DA-8159 and metformin, as both drugs are metabolized via hepatic CYP3A1/2 in rats. EXPERIMENTAL APPROACH: DA-8159 (30 mg kg(-1)) and metformin (100 mg kg(-1)), both separately and together, were administered to rats either intravenously or orally. The V (max), K (m), CL(int), apparent inhibition constants (K (i)), [I]/K (i) and concentrations of each drug in the liver and intestine were then measured. KEY RESULTS: After i.v. administration of both drugs simultaneously, the AUC of DA-8159 and metformin was significantly greater (21.2 and 33.9% increase for DA-8159 and metformin, respectively) than that of each drug alone. After p.o. administration of the drugs, the AUC of metformin was also significantly greater (20.7% increase) in the presence of DA-8159 than in its absence. However, the AUC of DA-8159 was similar in the absence and presence of metformin. CONCLUSIONS AND IMPLICATIONS: The significantly greater AUC of metformin and DA-8159 after i.v. administration of both drugs and of metformin after p.o. administration of both drugs is probably due to competitive inhibition for the metabolism of these drugs via hepatic CYP3A1/2. However, the similar AUCs of DA-8159 in the absence and presence of metformin, after p.o. administration, indicates that the dose of metformin used was insufficient to inhibit the hepatic and intestinal metabolism of DA-8159.     

Involvement of p38 MAP kinase-mediated cytochrome c release on sphingosine-1-phosphate (S1P)- and N-monomethyl-S1P-induced cell death of PC12 cells

d-erythro-Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, affects various neuronal functions including cell fate. S1P appears to have contradictory effects in PC12 cells, a neuronal model cell line; neurite retraction and cell survival/differentiation. In the present study, we examined whether S1P induces cell death in undifferentiated PC12 cells. Culture with S1P at 20 microM for 4 h caused lactate dehydrogenase leakage 24 h later. The response was reduced by an inhibitor of caspases and accompanied by the release of cytochrome c and DNA fragmentation. S1P caused the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) within 10 min. An inhibitor of p38 MAPK (10 microM SB203580) inhibited both the release of cytochrome c and DNA fragmentation induced by S1P. Treatment with nerve growth factor or pertussis toxin (PTX) decreased S1P-induced phosphorylation of p38 MAPK and cell death. These findings suggest that S1P-activated p38 MAPK acts as a death signal upstream of the release of cytochrome c. N-Monomethyl-S1P (MM-S1P), a weak agonist in cells expressing S1P1 receptors, had marked effects (phosphorylation of p38 MAPK, release of cytochrome c and DNA fragmentation) at lower concentrations than S1P and in a PTX-sensitive manner. These findings show that the activation of S1P receptors by S1P and MM-S1P causes cell death accompanied by DNA fragmentation via the p38 MAPK pathway-mediated release of cytochrome c in PC12 cells. The potential of S1P and MM-S1P to act as agonists of S1P receptors and as intracellular messengers is discussed.     

Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach

BACKGROUND AND PURPOSE: Tesofensine is a centrally acting drug under clinical development for Alzheimer's disease, Parkinson's disease and obesity. In vitro, the major metabolite of tesofensine (M1) displayed a slightly higher activity, which however has not been determined in vivo. The aims of this investigation were (i) to simultaneously accomplish a thorough characterization of the pharmacokinetic (PK) properties of tesofensine and M1 in mice and (ii) to evaluate the potency (pharmacodynamics, PD) and concentration-time course of the active metabolite M1 relative to tesofensine and their impact in vivo using the PK/PD modelling approach. EXPERIMENTAL APPROACH: Parent compound, metabolite and vehicle were separately administered intravenously and orally over a wide dose range (0.3-20 mg kg(-1)) to 228 mice. Concentrations of tesofensine and M1 were measured; inhibition of the dopamine transporter was determined by co-administration of [(3)H]WIN35,428 as the pharmacodynamic measure. KEY RESULTS: Pharmacokinetics of tesofensine and M1 were best described by one-compartment models for both compounds. Nonlinear elimination and metabolism kinetics were observed with increasing dose. The PK/PD relationship was described by an extended E(max) model. Effect compartments were used to resolve observed hysteresis. EC(50) values of M1, as an inhibitor of the dopamine transporter, were 4-5-fold higher than those for tesofensine in mice. CONCLUSIONS AND IMPLICATIONS: The lower potency of M1 together with approximately 8-fold higher through steady-state concentrations suggest that M1 did contribute to the overall activity of tesofensine in mice.     

Gender difference in the pharmacokinetic interaction between oral warfarin and oxolamine in rats: inhibition of CYP2B1 by oxolamine in male rats

The possible reason for the significantly greater AUC of oral warfarin with oral oxolamine in male Sprague-Dawley rats was evaluated. After oral administration of warfarin at a dose of 2 mg/kg to male rats with oxolamine at doses of 10 and 50 mg/kg, the AUC values of warfarin were significantly greater than the controls (254 and 330 versus 180 microg h/ml). However, the AUC values of warfarin were not affected by oxolamine in female rats. This could be due to inhibition of CYP2B1, 2C11 and 3A2 by oxolamine in male rats, since warfarin was metabolized via CYP1A1, 2B1, 2C6, 2C11 and 3A2 in rats and CYP2B1 is male dominant, and CYP2C11 and 3A2 are male specific. Therefore, phenytoin, torasemide and clarithromycin (mainly metabolized via CYP2B1/2, 2C11 and 3A2 in rats, respectively) were administered intravenously to male rats with or without oral oxolamine. After oral oxolamine at doses of 10 and 50 mg/kg, the AUC of phenytoin was significantly greater (1280 and 1640 versus 938 microg min/ml), however, the AUC values of torasemide and clarithromycin were independent of oxolamine. The above data suggest that the significantly greater AUC of oral warfarin with oral oxolamine could be due to inhibition of CYP2B1/2 by oxolamine in male rats.     

Simultaneous determination of tanshinones and polyphenolics in rat plasma by UPLC‐MS/MS and its application to the pharmacokinetic interaction between them

The aim of this study was to investigate the pharmacokinetic interaction between tanshinones and polyphenolics which act as the main bioactive compounds in Saliva miltiorrhiza Bunge (SMB). Thus, a rapid and highly sensitive ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) method was developed and validated to determine the concentrations of Tanshinone IIA (TSIIA), Tanshinone I (TI), Cryptotanshinone (CT), Salvianolic acid B (Sal B), Protocatechuic aldehyde (PAL), Rosmarinic acid (RA), and Danshensu (DSS) in rat plasma. The Sprague–Dawley rats were allocated to three groups which orally administered tanshinones (DST), polyphenolics (DFS), and a mixture of tanshinones and polyphenolics (DTF). These samples were processed by a simple liquid‐liquid extraction (LLE) method with ethyl acetate. Chromatographic separation was achieved on an Acquity BEH C₁₈ column (100 mm × 2. 1 mm, 1.7 µm) with the mobile phase consisting of 0.1% (v/v) formic acid and acetonitrile by gradient elution at a flow rate of 0.4 mL/min. The detection was performed on a triple quadrupole‐tandem mass spectrometer TQ‐MS/MS equipped with negative and positive electrospray ionization (ESI) interface in multiple reaction monitoring (MRM) mode. The statistical analysis was performed by the Student's t‐test with P ≤ 0.05 as the level of significance. The method showed good precision, accuracy, recovery, sensitivity, linearity, and stability. The pharmacokinetic profiles and parameters of these polyphenolics changed when co‐administrated with tanshinones. The tanshinones improved the bioavailability of DSS, accelerated the eliminating rate of RA and Sal B and promoted their distribution in vivo. They also contributed to promoting the biotransformation of Sal B to DSS. The polyphenolics could affect the pharmacokinetic of tanshinones, especially CT and TSIIA. Furthermore, the biotransformation of CT to TSIIA and the bioavailability of TSIIA were both improved. This study may provide useful information to avoid unexpected increase of the plasma drug concentration in the clinical practice. Copyright © 2015 John Wiley & Sons, Ltd.