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OBJECTIVES@#Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM).@*METHODS@#A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups.@*RESULTS@#The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population.@*CONCLUSIONS@#Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.
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Humans , Diabetes Mellitus, Type 2/drug therapy , Metformin/therapeutic use , Acidosis, Lactic , Tandem Mass Spectrometry , Hypoxia , GlucoseABSTRACT
AIM: To investigate the bioequivalence of domestic olmesartan medoxomil tablets and imported olmesartan medoxomil tablets (Benicar) in Chinese healthy subjects in fasting state. METHODS: This is an open, random and two-way crossover clinical trial involved 24 healthy subjects. A single oral dose 20 mg of domestic olmesartan medoxomil tablets (test preparation) and imported olmesartan medoxomil tablets (control preparation) was administrated under the condition of fasting. The plasma concentrations of olmesartan were determined by LC-MS/MS. The pharmacokinetics parameters were calculated and the bioequivalence of two formulations were evaluated by WinNonlin7.0 program. RESULTS:The main pharmacokinetic parameters of the test and control preparation were as follows: Cmax (702.08±149.24) vs.(706.50±127.00) μg/L; tmax 1.98 (1.33-4.00) vs. 1.98 (1.33-3.50) h; AUC0-t (4 516.93±995.07) vs. (4 543.74±818.45) μg•h•L-1; AUC0-∞ (4 578.16±1 005.73) vs. (4 605.70±820.54) μg•h•L-1; t1/2 (8.00±1.07) vs. (7.94±1.30) h, respectively. The 90% confidence limit of test preparation of the logarithmic transformed parameters Cmax, AUC0-t and AUC0-∞ were in 92.33%-105.29%, 91.86%-105.26%, 91.89%-105.16% vs. the reference preparation, respectively.CONCLUSION: The developed and validated method is rapid, sensitive, selective and reliable for the determination of olmesartan in human plasma; the domestic olmesartan medoxomil tablets are bioequivalence to the imported olmesartan medoxomil tablets.
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OBJECTIVE:To establish population pharmacokinetics(PPK)model of vancomycin so as to evaluate the effects of cystatin C(Cys C)on the pharmacokinetics parameters of vancomycin. METHODS:Totally 333 times therapeutic drug monitoring (TDM)were retrospectively collected from 225 patients who received vancomycin. Using sex,age,body weight(mT),Scr and Cys C as covariates,PPK model was established by using nonlinear mixed effect model method. Bootstrap method and normal prediction distribution error(NPDE)method were adopted for internal validation of model. Forty times of TDM data were collected from other 27 patients for external validation. Predicted accuracy and precision of model were investigated with mean prediction error (MPE) and root mean square error (RMSE). The effects of Cys C change on pharmacokinetic parameters of vancomycin were evaluated with steady state trough concentration and apparent clearance rate (CL/F) of vancomycin in typical patient (65 year-old,64 kg,Scr 66 μmol/L,1 000 mg,q12 h)forecasted with the final model at different levels of Cys C. RESULTS:CL/F of vancomycin was significantly influenced by age,body weight,the levels of Scr and Cys C. The final model was CL/F(L/h)＝3.68×(Scr/66)－0.431×(mT/64)1.1×(Age/65)－0.368×(Cys C/1.04)－0.693,V/F was equal to 82.5 L. The robust rate verified by Bootstrap method was 100%. Except for the interindividual variation of V/F,the relative bias of other pharmacokinetic parameters was less than 5%,and the estimated parameters of the final model were in the 95% confidence intervals of estimated values of Bootstrap. NPDE results showed that the homogeneity of variance was consistent with normal distribution (P＞0.05). In external validation,MPE and RMSE of the simplest model were －1.52 μg/mL and 6.87 μg/mL. MPE and RMSE of the final model were －0.32 μg/mL and 4.27 μg/mL,the accuracy and precision were improved significantly in the final model. When Cys C levle of typical patient was 0.3-4.0 mg/L,the steady state trough concentration predicted by final model were 5.25-29.97 μ g/mL and CL/F were 1.45-8.71 L/h. CONCLUSIONS:Age,body weight,the levels of Scr and Cys C significantly influence the pharmacokinetic parameters of vancomycin;moreover,the level of Cys C can change blood concentration of vancomycin. Established PPK model is of great predictive performance,which can be used to estimate the individual pharmacokinetics parameters of vancomycin.
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Objective To discuss the value of dynamic contrast-enhanced MRI (DCE-MRI)in differential diagnosis of high-grade gliomas (HGG)and metastasis.Methods 27 cases of HGG and 46 cases of metastasis were enrolled.All patients took contrast MRI and DCE-MRI before operation.Using the pharmacokinetic model of Extended Tofts Linear to quantitative analyze the data,volume transfer constant (Ktrans ),extracellular extravascular volume fraction (Ve )and blood plasma fraction (Vp )of the lesion's solid components and perilesional edam were obtained.Ktrans value,Ve value and Vp value were compared to judge whether there were significant differences between the two kinds of tumors.Results The values of the Ktrans ,Ve and Vp in parenchyma of HGG and metastasis were not statistically significant (P >0.05).The values of Ktrans and Ve in peritumoral edema of HGG were significantly higher than that of metastasis (P <0.05);Vp values in the peritumoral edema of HGG were lower than that of metastasis,but the difference was not statistically significant (P >0.05). Conclusion DCE-MRI can effectively distinguish HGG from metastasis through quantitative analysis of the perilesional edema.
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Objective To discuss the value of dynamic contrast-enhanced MRI (DCE-MRI)in differential diagnosis of high-grade gliomas (HGG)and metastasis.Methods 27 cases of HGG and 46 cases of metastasis were enrolled.All patients took contrast MRI and DCE-MRI before operation.Using the pharmacokinetic model of Extended Tofts Linear to quantitative analyze the data,volume transfer constant (Ktrans ),extracellular extravascular volume fraction (Ve )and blood plasma fraction (Vp )of the lesion's solid components and perilesional edam were obtained.Ktrans value,Ve value and Vp value were compared to judge whether there were significant differences between the two kinds of tumors.Results The values of the Ktrans ,Ve and Vp in parenchyma of HGG and metastasis were not statistically significant (P >0.05).The values of Ktrans and Ve in peritumoral edema of HGG were significantly higher than that of metastasis (P <0.05);Vp values in the peritumoral edema of HGG were lower than that of metastasis,but the difference was not statistically significant (P >0.05). Conclusion DCE-MRI can effectively distinguish HGG from metastasis through quantitative analysis of the perilesional edema.
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To study the effects of sanguisorba tannins and saponins compatibility at different proportions [tannins-saponins (1∶1) and tannins-saponins(8∶1)] after intragastric administration (50 mg•kg⁻¹) on pharmacokinetic parameters of catechin, epicatechin and ziyuglycoside Ⅰ in rats by using pharmacokinetic techniques and methods. Kinetica 5.0 software was used to calculate the pharmacokinetic parameters. The results showed that the specificity, linearity, recovery rate, precision and stability of the established detection method were in line with the test requirements. When the sanguisorba tannins and eaponins were combined at the rate of 1∶1, Vd and CL of catechin and epicatechin were increased significantly（P<0.05); MRT was significantly shortened(P<0.05); Cmax and AUC were significantly reduced(P<0.05). When the sanguisorba tannins and saponins were combined at the rate of 8∶1, Vd and CL of catechin and epicatechin were significantly reduced(P<0.05); MRT was significantly prolonged(P<0.05); Cmax and AUC were increased significantly(P<0.05). In addition, with the increase in proportion of sanguisorba tannins in the compatibility, Cmax and AUC of ziyuglycoside Ⅰ were increased significantly(P<0.05); Vd and CL were significantly reduced(P<0.05), Tmax was obviously lagging behind, and MRT was also significantly prolonged(P<0.05). In our present study, catechin, epicatechin and ziyuglycoside Ⅰ showed good pharmacokinetic behavior in rats when sanguisorba tannins and saponins were combined at the rate of 8∶1 in compatibility, which could be used as a reference for the proportion in sanguisorba tannins and saponins compatibility.
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OBJECTIVE:To determine plasma concentration of caffeine,dapsone and chlorzoxazone in rats,and to calculate pharmacokinetic parameters. METHODS:6 rats were given the mixture of caffeine,dapsone and chlorzoxazone intragastrically, 1.5,2 and 3 mg/kg,respectively. 0.2-0.3 ml blood were collected before medication and 0.5,1,2,3,4,6,8,12,24 h after medication.The plasma sample was treated with solid phase extraction. The plasma concentration of caffeine,dapsone and chlorzoxa-zone were determined by HPLC using N-(2-Hydroxyethyl) phthalimide as internal standard. The pharmacokinetic parameters were calculated using DAS 2.0 software. RESULTS:The linear ranges of caffeine,dapsone and chlorzoxazone were all 0.2-30 μg/ml (r were 0.996 4,0.996 1,0.998 8,respectively). The limit of quantitation were 0.2 μg/ml. The recoveries of low-concentration, medium-concentration and high concentration were(84.8±3.6)%-(111.4±10.2)%(RSD were 4.3%-9.8%,n=3),(107.0±13.3)%-(113.5±8.1)%(RSD were 7.1%-14.0%,n=3),(104.2±10.8)%-(111.1±12.2)%(RSD were 8.0%-11.0%,n=3). Pharmacoki-netic parameters were as follows as tmax(1.70±0.99),(1.50±1.00),(1.92±0.80)h;t1/2(0.73±0.22),(2.77±1.35),(2.78±2.34) h;cmax (2.60 ± 0.50),(5.78 ± 1.19),(9.76 ± 1.37) mg/L;AUC0-t (8.43 ± 0.79),(20.68 ± 1.91),(26.71 ± 2.45) mg·h/L(n=6). CONCLUSIONS:The method is simple,sensitive and accurate,and can be used for the plasma concentration determination and pharmacokinetic study of caffeine,dapson and chlorzoxazone.
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Pharmacokinetics (PK) is the science of the kinetics of drug absorption, distribution and elimination. Statistical methods are usually used for PK parameter estimation producing nonlinear responses where drug effect mechanism is modeled using compartmental approach. In the present study, PK parameters were estimated with nonlinear fixed effects one compartment open model where drug dose and sampling time are covariates and the plasma drug concentration is dependent variable. The PK parameters namely absorption rate constant (a), elimination rate constant (b) and apparent volume of distribution (V) were estimated using nonlinear least square method for each individual separately and for all individuals collectively with longitudinal or multiple response plasma drug concentration-time data obtained from 24 healthy human volunteers with reference drug product of Atorvastatin. The estimates for combined data were â =0.13±0.13hr-1, =0.49±0.13hr-1, =248±0.05L. All the individuals were again stratified into three categories based on Body Mass Index (BMI) and the PK parameters were estimated for each stratum accordingly (stratum-normal: â=0.12±0.17hr-1, =0.47±0.17hr-1, =250.24±0.07L; stratum-overweight: â =0.15±0.24hr-1, =0.47±0.25hr-1, =267.25±0.09L; stratumunderweight: â =0.13±0.13hr-1, =0.49±0.13hr-1, =245±0.05L).
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The purpose of the present study was to investigate the biodistribution profile of the venom of Hemiscorpius lepturus, the most dangerous scorpion in Iran. Blood and tissue samples were taken at various predetermined intervals during a 400-minute period for the venom and a 360-minute period for the antivenom in rats. The radio-iodination was carried out using the chloramine-T method. The results showed that the descending order of venom uptake was skin, kidneys and intestine, respectively. The descending order of polyclonal antivenom uptake was kidneys, intestine, heart and lungs. The calculated pharmacokinetic parameters of the venom were Telimination half-life = 521.5 ± 12.6 minutes; Vd/F (apparent volume of distribution) = 14.9 ± 3.3 mL; clearance (CL/F, apparent total clearance of the drug from plasma) 0.02 ± 0.005 mL/minute and for the antivenom Telimination half-life = 113.7 ± 7.4 minutes; Vd/F = 13 ± 1.2 mL and CL/F 0.08 ± 0.01 mL/minute. The pharmacokinetics profile comparison of the venom with that of the antivenom shows that serotherapy may be more effective if administered within 2-4 hours following envenomation by H. lepturus.(AU)
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Scorpion Venoms , AntiveninsABSTRACT
The pharmacokinetic behaviour of the non-glycosylated, bacterially-derived recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and the glycosylated mammalian product was studied after intra and extra vascular administration of a single dose in rodents. Each route of administration gave a different rhGM-CSF concentration-time profile. After extra vascular administration of equivalent doses, a higher peak concentration and faster elimination were observed in the group treated with the E. coli-derived cytokine. The faster elimination resulted in a return to pre-treatment plasma levels after 12 hrs, versus 48 hrs following the administration of glycosylated rhGM-CSF. After intravascular administration, clearance of rhGM-CSF was significantly decreased by the presence of carbohydrates. Non-significant differences in the terminal phase of the biphasic kinetics were found, but the distribution phase was significantly longer for the glycosylated form
Subject(s)
Animals , Female , Mice , Rats , Granulocyte Colony-Stimulating Factor/pharmacokinetics , Cells, Cultured , Dose-Response Relationship, Drug , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/isolation & purification , Granulocyte Colony-Stimulating Factor/blood , Glycosylation , Injections, Intraperitoneal , Injections, Intravenous , Mice, Inbred BALB C , Reference Standards , Recombinant Proteins/pharmacokinetics , Rats, Wistar , Time Factors , Tissue DistributionABSTRACT
OBJECTIVE: To design the dosage regimen of aminophylline using reported pharmacokinetic parameters (mean group value). METHODS: The calculation of oral maintain dose, the infusion rate of intravenous drip maintain dose and the loading dose of intravenous drip were introduced. RESULTS: Different dose were required for different pathophysiological conditions insteading of aminophylline 200 mg three times a day (p.o.) for every patient. CONCLUSION: It is recommended that all hospitals which are unable to determine plasma concentration should design dosage regime of aminophylline using pharmacokinetic parameters.
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OBJECTIVE:To compare the bioequivalence of 2 kinds of Omeprazole enteric-coated capsules. METHODS: A single dose of Omeprazole enteric-coated capsules was given to 18 healthy volunteers by randomized crossover method, and the plasma concentrations of omeprazole were determined by HPLC. The pharmacokinetic parameters were calculated with 3p97 pharmacokinetic program and the bioequivalence was evaluated. RESULTS: The plasma concentration-time curve of two preparations fitted to one-compartment model. The pharmacokinetic parameters of test preparation vs. reference preparation were as follows: Cmax(1.69?1.00) ?g?mL-1 vs. (1.71?1.02) ?g?mL-1; tmax(3.22?1.11)h vs. (3.06?1.00)h; AUC0～24(8.42?4.38) ?g?h?mL-1 vs. (8.87?5.32) ?g?h?mL-1; AUC0～∞(10.35?5.01) ?g?h?mL-1 vs. (10.81?5.86) ?g?h?mL-1. The relative bioavailability of Omeprazole enteric-coated capsules was(94.93?14.54)%.CONCLUSION:2 kinds of Omeprazole enteric-coated capsules are bioequivalent.
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Objective To establish a HPLC method for the determnation of serum concentration of isoimperatorin in rats and study pharmacokinetic characteristic of isoimperatorin in rat after drug admiaistraction. Method The concentrations of isoimperatorin in rats were determined after drug administration and the pharmacokinetic parameters of isoimperatorin were estimated by DAS2.0 computer program. Result The concentration-time profiles were fitted with open two compartment model system. The main pharmacokinetic parameters were as follows:Tmax =(1.6?0.000)h, Cmax =(15.842?0.35)mg/L, AUC0-t=(80.761?10.03)mg/(L?h), AUC0-∞=(89.45?9.34)mg/(L?h), t1/2=(5.101?0.24)h. Conclusion The method is appropriate for the determination and pharmacokinetic study of isoimperatorin in rats after drug administration.
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OBJECTIVE: To study the distribution characteristics of paeonol in the plasma and brain tissue of mice.METHODS: The concentrations of paeonol in the plasma and brain tissue of mice were determined by GC-MS and the pharmacokinetic parameters of paeonol calculated with 3P97 software were compared and evaluated.RESULTS: The main pharmacokinetic parameters of paeonol in the plasma and the brain were as follows: Ka:(99.3 h-1 vs 18.22 h-1);t1/2?:(0.04 h vs 0.05 h);t1/2?:(3.95 h vs 71.23 h);t1/2ka:(0.01 h vs 0.04 h);Cmax:(4.57 ?g?mL-1 vs 0.51 ?g?g-1);AUC0→t∶2.32 ?g?mL-1?h,1.62 ?g?g-1?h.CONCLUSION: After intragastric administration,paeonol rapidly absorbed by mice and quickly eliminated from plasma,and it had difficulty in passing through the blood-brain barrier but it has long retention time in brain tissue.
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PURPOSE: Mycophenolate mofetil (MMF) given orally as 1000 mg twice daily has shown to be effective in the suppression of acute allograft rejection following renal transplantation. However, Korean transplant patients are usually administered with a lower dose of MMF (1~1.5 gm/day) than the recommended dose due to high incidence of gastrointestinal intolerance. The purpose of this study was to characterize the pharmacokinetic parameters of the mycophenolic acid (MPA), the active form of MMF, in Korean kidney transplant recipients. METHODS: The plasma MPA concentrations of 10 Korean kidney transplant recipients (7 men and 3 women) administered with a suboptimal dose of MMF (750 mg twice a day) were measured at 2 weeks of the MMF therapy by HPLC method. RESULTS: Plasma MPA concentration-time curve pattern of patients taking lower doses of MPA was consistent with previously reported profiles of patients taking the fully recommended doses. The plasma MPA concentration-time curve was characterized by an early sharp peak within 1 hour and a small second peak in some patients at 4~12 hours postdose. The mean ( SD) Cmax was 8.73 4.65micro gram/ml, and the mean MPA AUC was calculated as 18.45 4.25micro gram hr/ml. The mean fraction of free MPA, which is pharmacologically active, was 1.60 0.23% and this value seemed similar to previously reported data. The patient's age, weight, body surface area, and renal function did not influence the MPA AUC. However, a difference in AUC according to sex was statistically significant (P=0.0227). Free fraction of MPA appeared not to be affected by serum albumin and renal function when creatinine clearance was above 40 ml/min. Correlation analysis between each plasma concentration and AUC for the limited strategy of MMF therapeutic drug monitoring (TDM) resulted that the concentrations of predose, 1 hr post-dose, and 8 hr post-dose were positively related with AUC value, and their coefficients of correlation were 0.74545 (P=0.0133), 0.68485 (P=0.0289), and 0.63636 (P=0.0479), respectively. CONCLUSION: This study have shown that the pattern of the time-concentration profile of MPA was similar to the results of other studies performed with Caucasians, although there was interindividual variability of MPA AUC, Cmax, and Tmax.
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Humans , Male , Allografts , Area Under Curve , Body Weight , Chromatography, High Pressure Liquid , Creatinine , Drug Monitoring , Incidence , Kidney Transplantation , Kidney , Mycophenolic Acid , Plasma , Serum Albumin , TransplantationABSTRACT
OBJECTIVE:To direct rational use of drugs in the clinic by applying pharmacokinetic theory.METHODS:A new formula practicable for clinic was derived by expanding and transforming the basic pharmacokinetic formula.A practical pharmacokinetic parameter table was established and from which the pharmacokinetic parameters needed by clinic were avail?able.RESULTS:With the help of practical pharmacokinetic parameter table,the rationality of clinical medication can be in?vestigated at any time.Combined with monitoring of blood concentration,personalized medicine can be realized.CONCLU?SION:The practical pharmacokinetic parameter table is an important tool in directing personalized medicine.
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In calculating pharmacokinetic parameters, Subjective bias may be induced by using the method of residuals. This paper reports a nonlinear least squares fitting program which may be adapted in APPLE II microcomputer. The program can not only increase the precision of estimated parameters, but also provide objective criteria e.g. Akaike's Information Criterion ( AIC ) for determining which kind of compartment model is most appropriate. Furthermore, the standard error of parameter is calculated which gives the variability of the estimation. The use of this program is guided on-screen prompts that display Some form of menu including the various types of compartmental models for intra and extravascular administration. The data can be stored or drawn out from the disk and the plot of curve fitting is readily feasible.