Pharmacokinetic comparison with different assays for simultaneous determination of cis-,trans-cefprozil diastereomers in human plasma / 药物分析学报

The purpose of this study was to compare pharmacokinetic (PK) parameters obtained using two newly developed assays,HPLC-UV and UPLC-ESI-MS/MS.Selection of assay and results obtained therefrom are very important in PK studies and can have a major impact on the PK-based clinical dose and usage settings.For this study,we developed two new methods that are most commonly used in biosample analysis and focused on PK parameters obtained from them.By HPLC-UV equipped with a Luna-C8 column using UV detector,cefprozil diastereomers were separated using water containing 2％ (V/V) acetic acid and acetonitrile as a mobile phase.By UPLC-ESI-MS/MS equipped with a HALO-C18column,cefprozil diastereomers were separated using 0.5％ (V/V) aqueous formic acid containing 5 mM ammonium-formate buffer and methanol as a mobile phase.Chromatograms showed high resolution,sensitivity,and selectivity without interference by plasma constituents.Both intra-and inter-day precisions (CV,％)were within 8.88％ for HPLC-UV and UPLC-ESI-MS/MS.Accuracy of both methods was 95.67％-107.50％.These two analytical methods satisfied the criteria of international guidance and could be successfully applied to PK study.Comparison of PK parameters between two assays confirmed that there is a dif-ference in the predicted minimum plasma concentrations at steady state,which may affect clinical dose and usage settings.Furthermore,we confirmed possible correlation between PK parameters and various biochemical parameters after oral administration of 1000 mg cefprozil to humans.

Determination of pharmacokinetic parameters of omeprazole based on distribution equilibrium / 西安交通大学学报(医学版)

Objective: To determine the pharmacokinetic parameters based on distribution equilibrium theory by establishing the blood drug concentration-time curve of single elimination phase. Methods:Rats were intravenously infused with omeprazole at andante constant rate. Blood was collected at different time points during infusion, and drug concentration in plasma was detected by HPLC. Pharmacokinetic parameters were calculated with GraphPrism 6.0 software. Results: The concentration-time curve of omeprazole during intravenous infusion showed a first-order exponential relationship. The increase of plasma omeprazole concentration was rapid at the initial stage of the infusion and then became gradually slow as time went on. After 5 half lives a steady state was reached. The elimination rate constant (K) of omeprazole in rats was (2.95±0.67)h-1. The half-life was (15±4)min. The apparent volume of distribution was (0.30±0.17)L, and the drug clearance was (0.83±0.33)L/h. Conclusion: The distribution of the drug in the body is basically balanced during the process of andante constant-rate intravenous infusion, and there is no interference of distribution. The measured pharmacokinetic parameters are closer to the reality.

PKconverter: R package to convert the pharmacokinetic parameters

Population pharmacokinetic analysis and modeling procedures typically require estimates of both population and individual pharmacokinetic parameters. However, only some of these parameters are contained in models and only parameters in the model can be estimated. In this paper, we introduce a new R package, PKconverter, to calculate pharmacokinetic parameters using the relationships among them. After fitting the model, other parameters can be calculated from the functional relationship among the parameters. PKconverter provides the functions to calculate whole parameters along with a Shiny application for converting the parameters. With this package, it is also possible to calculate the standard errors of the other parameters that are not in the model and estimate individual parameters simultaneously.

How to design intravenous anesthetic dose regimens based on pharmacokinetics and pharmacodynamics principles

Pharmacokinetics is the study of the rate and degree of drug transport to various tissues in the human body. Pharmacokinetic parameters summarize drug kinetics and ideally predict a clinical situation. A single kinetic profile may be summarized by peak concentration, peak time, half-life and area under the curve. Dosage regimens are designed to confer the maximum desired effects for the required time period with minimal toxicity. Target-controlled infusions use pharmacokinetic models to titrate intravenous anesthetic administration to achieve a desired drug concentration. Context-sensitive half time is used to predict the clinical time course, rather than terminal half-life. It is important that anesthesiologists understand the basic pharmacological principles and apply them in their daily clinical practice. This review discusses the ways in which anesthesiologists can design a patient-specific dosage regimen of intravenous anesthetics by utilizing basic concepts of pharmacokinetics and pharmacodynamics using pharmacokinetic simulations.

Pharmacokinetics in rabbits of oxybutynin hydrochloride ethosomal gel / 中国药学杂志

OBJECTIVE: In vivo study on the oxybutynin hydrochloride (OXB) ethosomal gel in rabbits was carried out to obtain pharmacokinetic parameters in comparison to contrast gel. METHODS: After transdermal administration in rabbits of the OXB ethosomal gel and contrast gel respectively, OXB in the plasma was determined by HPLC-MS, the pharmacokinetic parameters were calculated with DAS 2.1.1. RESULTS: Dose of OXB for 20 mg in the ethosomal gel and for 50 mg in contrast gel transdermal delivery, the AUC0→48 of ethosomal gel and contrast gel were 597.63, 518.40 ng · h · mL-1, ρmax were 27.91, 29.81 ng · mL-1, and tmax were 6.67, 4.67 h respectively. A relative bioavailability of OXB ethosomal gel was 288.4% compared with contrast gel. CONCLUSION: In vivo experiments indicate that the OXB ethosomal gel not only reduce the drug dosage, but also show good bioavailability in rabbits.

Study on Pharmacokinetics of the Sustained-release Tablets and Common Tablets of Melatonin in Beagle Dogs in Vivo / 中国药房

OBJECTIVE:To compare pharmacokinetic parameters of the common tablets and sustained-release melatonin tablets in beagle dogs in vivo.METHODS:The blood concentration of melatonin of6Beagle dogs was determined by HPLC and the pharmacokinetic parameters were calculated with3p97software after administered random crossover with single dose of sustained-release melatonin tablets6mg or the common tablets3mg.RESULTS:The concentration-time curves of both the common tablets and sustained-release melatonin tablets were in conformity with two-compartment model,C max of common tablets and sustained-release tablets were(11.27?3.77)ng/ml and(8.31?5.11)ng/ml respectively,t max of which were(0.50?0.18)h and(1.00?0.37)h respectively,t 1/2ke of which were(1.21?0.52)h and(3.27?0.89)h,AUC 0～t of which were(25.23?7.71)(ng?h)/ml and(38.03?16.45)(ng?h)/ml respectively.CONCLUSION:Compared with the common tablets,the sustained-release tablets showed slower absorption,longer peak time,lower peak concentration,slower elimination and longer duration.

Relationship of Propranolol Pharmacokinetic Parameters with Portosystemic Shunt in CCl4-induced cirrhotic Rats / 대한간학회지

BACKGROUND: This study was designed to determine the relationship of propranolol pharmacokinetic parameters with portosystemic shunt in CCl4-induced cirrhotic rats. METHODS: Cirrhotic rats(n=6) were induced by intramuscular injection of CCl4 in olive oil(two time per weeks) for 12 weeks. Controls (n=6) were injected intramuscularly with the same dose of olive oil for 12 weeks. We evaluated the amount of portosystemic shunt by thallium-201 per rectal scintigraphy. After intravenous bolus injection of propranolol (2mg/kg) to rats, the serum propranolol concentrations were analyzed by a HPLC-fluorimetric detector system. Pharmacokinetic parameters such as C0, AUC, t(1/2(beta)), and CLp were determined in each group. Then, a small amount of heptic tissue was obtained and subjected to determination of the hepatic collagen content by quantitating 4-hydroxyproline and were inspected by microscope after hematoxylin and eosin stain. RESULTS: In liver biopsy, liver fibrosis progressed in CCl4-induced cirrhotic rats. The serum concentrations of propranolol were significantly (p < 0.01) elevated in CCl4-induced cirrhotic rats. Mean amount of 4-hydroxyproline, mean H/L ratio, and mean AUC in CCl4-induced cirrhotic rats was significantly (p < 0.01) higher than that in control rats. There was a relationship between AUC, H/L ratio, and amount of 4-hydroxyproline. CONCLUSION: H/L ratio may help in the selection of drug dosage (especially blood flow dependent drug) in pre-clinical studies for chronic liver disease during the drug development process.

Development of the Data Processing Program of Digoxin and Adjustment of Effective Blood Drug Concentration Range / 中国药房

OBJECTIVE:To develop the data processing program of Digoxin blood drug concentration(DBDP)and to determine the range of effective blood concentration of Digoxin.METHODS:The DBDP program was developed by VISUAL BASIC6.0and run in Windows95system.The data of blood drug concentration,which was determined with flurescence polarization immunoassay(FPIA)in our hospital,was analyzed with DBDP program and effective blood drug concentration range of Digoxin was set up.RESULTS:The DBDP program integrated functions including pharmacokinetic parameter estimation,establishment of the effective blood drug concentration range,management of the data of the blood drug concentration moni?toring,automatic addition of patient's file,multifunctional fuzzy searching,retrospective analysis and clinical query about drug use.The effective blood drug concentration range of Digoxin was0.58～2.01ng/ml.CONCLUSION:The DBDP program is a very practical tool for the development of therapeutic drug monitoring and it is very necessary to develop blood drug concen?tration monitoring and establish the effective blood drug concentration range.

Changes of Propranolol Pharmacokinetic Parameters According to Hepatic Fibrotic Severity in CCl4-Treated Rats / 대한간학회지

BACKGROUND/AIMS: This study was designed to determine the effect of hepatic fibrotic severity on pharmacokinetics of propranolol in CCl4-treated rats. METHODS: 1 mL/kg of 10% CCl4 in olive oil was injected intramuscularly to rats twice weekly for 4, 6, 8 and 10 weeks, respectively (n=6). Control (n=6) was a sham-injected equal dose of olive oil for 10 weeks. After intravenous bolus injection of 2 mg/kg propranolol to rats, the serum propranolol concentrations were analyzed for 4 hours at various time points by a HPLC-fluorimetric system, and pharmacokinetic parameters such as C0, MRT, AUC, Vdss, t1/2( ) and CLp were determined. Then, a small amount of hepatic tissue was obtained and subjected to determination of the hepatic 4-hydroxyproline content, which confirmed the hepatic fibrotic severity. RESULTS: The serum concentrations of propranolol at 0.5, 1, 2 and 4 hours were significantly increased in CCl4-treated rats (p<0.01). In proportion to the duration of CCl4 treatment, C0 and AUC were significantly increased, and Vdss and CLp were significantly decreased (p<0.001). But MRT and t1/2( ) were not significantly changed. The hepatic 4-hydroxyproline content was gradually increased in CCl4-treated rats (p<0.001). CONCLUSION: Gradual changes in pharmacokinetic parameters of propranolol were seen to be dependent on the hepatic fibrotic severity. We suggest that gradual dosage modification, according to their hepatic fibrotic severity, is necessary for many drugs administered to patients with chronic liver disease.

Evaluation of Marsh's Pharmacokinetic Parameter Set for Target Controlled Infusion of Propofol in Korean / 대한마취과학회지

BACKGROUND: Marsh's pharmacokinetic parameter set is the most widely used parameter for target controlled infusion for propofol. However, Marsh's model was derived from a European population, and it is uncertain whether this model is accurate for Koreans. METHODS: Thirty ASA 1 or 2 adult patients undergoing orthopedic surgery participated in this study. Atropine 0.5 mg was injected for premedication. Anesthesia was induced by a TCI of propofol with a target concentration of 6 microgram/ml and maintained around 3 - 5 microgram/ml according to the bispectral index (35 - 45). In the middle of surgery, target concentrations were increased to 6 microgram/ml and maintained until effect site concentration was the same concentration. Three minutes after equilibration, 3 ml of blood was drawn from the radial artery and contralateral antecubital cephalic vein for measuring blood concentration using HPLC. Target concentrations were gradually decreased at the interval of 1 microgram/ml until the end of surgery and a blood sample was drawn as described in the method. A sample for every 1 microgram/ml was collected in the recovery room. Performance error of the predicted concentration of blood was calculated. RESULTS: The performance error was -12.86 - 16.55% for 1 - 6 microgram/ml of predicted concentration. Measured concentrations were higher than predicted at higher concentrations, but lower at lower concentrations. Measured cardiac output and arteriovenous concentration differences at 1 - 6 microgram/ml showed no difference. CONCLUSIONS: Marsh's pharmacokinetic model was accurate for propofol TCI in Koreans in terms of relatively low performance error (< 20%) in the concentration range of 1 - 6 microgram/ml.

Effect of Ethanol on Pharmacokinetics of Phenytoin Sodium in Rabbits / 中国药房

OBJECTIVE:To study the effect of ethanol on the pharmacokinetics of phenytoin sodium in rabbits METHODS:The serum concentrations of phenytoin sodium at different points of time were determined by UV-spectrophotometry in eight rabbits after administration of phenytoin sodium(10mg/kg)alone and in combination with ethanol RESULTS:After administration in combination with ethanol,the AUC of phenytoin sodium was significantly decreased from(4 108 64?1 039 98)mg/(min L) to (1 903 65?1 003 40)mg/(min L),Cmax from(29 0?2 94)mg/L to(16 0?5 9)mg/L,T1/2(ke) from(98 45?26 4)min to(82 84?25 5)min;but the apparent distribution volume(Vd)was obviously increased from(0 3 475?0 0 360)L/kg to(0 6 819?0 1 901)L/kg and the clearance rate(CL) from(0 0 026?0 0 008)ml/(kg?min)to(0 0 062?0 0 022)ml/(kg?min) CONCLUSION:The elimination of phenytoin sodium was significantly accelerated after simultaneous administration of ethanol in rabbits