Population pharmacokinetics of naringin in total flavonoids of Drynaria fortunei (Kunze) J. Sm. in Chinese women with primary osteoporosis.

OBJECTIVE: To evaluate the effect of covariates on the pharmacokinetic profiles of naringin in the total flavonoids of Drynaria fortunei (Kunze) J. Sm. in the Qianggu Capsule () by evaluating Chinese women with primary osteoporosis. METHODS: A total of 98 female patients from the communities of Jingshan, Beixinqiao, Jiaodaokou, Chaoyangmen, and Donghuamen in Beijing, China, aged 40 to 80 years, were included in this study. Blood samples were collected before and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after a single oral dose of Qianggu Capsule. The concentration in blood samples from 32 patients before and 0.5, 1, 2, 3, and 4 h after drug administration were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and full set of pharmacokinetic data was analyzed with nonlinear mixed-effect modeling (NONMEM) software. The mean of population parameters clearance (C1), central distribution volume (V), absorption rate constant (Ka1), inter-compartmental clearance (C2), peripheral distribution volume (V2) were set as parameters and estimated through base model, covariate model, and final model. Age, height, weight, blood urea nitrogen (BUN), serum creatinine (Scr), alanine transaminase (ALT), aspartate transaminase (AST), hyperlipidemia, Liver (Gan) Kidney (Shen) yin insufficiency (GSYI), Kidney (Shen) yang insufficiency (SYI) were set as covariates. RESULTS: The relationships between these parameters and covariates were analyzed. The results showed that C1 was the main parameter influenced by the selected covariates among the population parameters, and the relationships between the covariates and C1 were analyzed, among the selected covariates hyperlipidemia was identified as significant covariate of C1. CONCLUSION: The pharmacokinetic behaviors of naringin are altered with hyperlipidemia in Chinese women with primary osteoporosis.

Role of arachidonoylethanolamine in blood pressure regulation in volume-resistant patients on peritoneal dialysis.

In this study we explored the possible role of arachidonoylethanolamine (AEA) in regulating blood pressure in patients on continuous ambulatory peritoneal dialysis (CAPD). One hundred and five patients on CAPD were enrolled. Volume status was evaluated by the overhydration (OH) value obtained by bioimpedance analysis. OH<2.0 kg was defined as normal volume (NV) and OH≥2.0 kg as high volume (HV). Home mean systolic blood pressure<130 mmHg was defined as controlled hypertension (CHT) and ≥130 mmHg as uncontrolled hypertension (UHT). The patients were divided into four subgroups: (1) controlled hypertension with normal volume (CHT-NV), (2) controlled hypertension with high volume (CHT-HV), (3) uncontrolled hypertension with normal volume (UHT-NV), and (4) uncontrolled hypertension with high volume (UHT-HV). AEA was measured by ultra performance liquid chromatography-tandem mass spectrometry. AEA was significantly higher in the HV group as compared with the NV group (P<0.05). In addition, AEA was also significantly higher in the CHT-HV group as compared with the UHT-NV group (P<0.05). These results may suggest a compensatory function of AEA and TRPV1 pathway to lower blood pressure during volume expansion in CAPD patients.

Effect of CYP2D6, CYP3A5, and MDR1 genetic polymorphisms on the pharmacokinetics of risperidone and its active moiety.

Clinical studies suggest that plasma levels of risperidone and its active moiety (risperidone + 9-hydroxyrisperidone) correlate with adverse drug effects. The aim of this study is to evaluate the pharmacogenetic variability in the disposition of risperidone and the active moiety in healthy Chinese subjects. A 2-mg single dose of risperidone is orally administered to 23 healthy Chinese subjects. The risperidone and 9-hydroxyrisperidone serum concentrations are measured. The polymorphic alleles of CYP2D6*10, CYP3A5*3, MDR1 C1236T, G2677T/A, and C3435T are determined in each subject. The mean maximum plasma concentration and area under the time-concentration curve extrapolated to infinity for risperidone are significantly higher in subjects possessing the CYP2D6*10 allele than in those with the CYP2D6*1/*1 and *1/*10 genotype. For active moiety, the subjects who carry both homozygous CYP2D6*10 and homozygous CYP3A5*3 have 98% higher area under the time-concentration curve extrapolated to infinity and 59% higher maximum plasma concentration compared with other CYP2D6 EM subjects. The MDR1 2677GA genotype may also play a role in risperidone pharmacokinetics. Further studies are needed to explore the impact of MDR1 2677GA and CYP3A5 polymorphisms on risperidone therapy.

Two-stage analysis of pharmacokinetics of sufentanil administered by target-controlled infusion in Chinese patients.

BACKGROUND: Sufentanil is a suitable choice for target-controlled infusion (TCI) because of its shorter context-sensitive half-time. The current study was to estimate the pharmacokinetics of sufentanil TCI in Chinese patients using the two-stage analysis. METHODS: Twelve adult patients with American Society of Anesthesiologists (ASA) physical status I or II undergoing elective surgery under general anesthesia were included. Anesthesia was induced with propofol, rocuronium and sufentanil administered by TCI lasting for 30 minutes, with target effect-site concentration of sufentanil 4 or 6 ng/ml. Frequent arterial blood samples (1.5 ml) were taken during and up to 24 hours after sufentanil TCI. Before the end of surgery, another arterial blood sample (1.0 ml) was drawn for the blood-gas analysis. Plasma sufentanil concentrations were determined by liquid chromatography-tandem mass spectrometry (limit of quantitation was 5 pg/ml). The data were analyzed with the two-stage approach, linear regression and correlation analysis. RESULTS: The pharmacokinetics of sufentanil TCI were adequately described by a three-compartment model. The variables were derived as follows: the volume of central compartment (V(1)) was 5.4 L, volume of distribution at steady-state (Vdss) was 222.6 L, metabolic clearance (Cl(1)) was 0.84 L/min and elimination half-life (t(1/2Y)) was 389 minutes. Patients' age, gender and PaCO2 correlated significantly with the pharmacokinetic parameters. The Vdss, volume of slowly equilibrating compartment (V(3)) and t(1/2Y) increased, and rapid distribution clearance (Cl(2)) decreased with increasing patient age. Male patients had larger values of Vdss, volume of rapidly equilibrating compartment (V(2)) and V(3) than female patients. The Vdss and V(3) increased with higher PaCO2 values. There were no significant correlations between the pharmacokinetic variables and body weight, height, lean body mass, plasma albumin, sufentanil dose, duration of surgery, pH or base excess of blood (BE-B). CONCLUSIONS: The pharmacokinetics of sufentanil TCI in Chinese patients can be optimally described by a three-compartment model. The pharmacokinetic analysis technique may affect the pharmacokinetic parameters and correlations.

Pharmacokinetics of sufentanil administered by target-controlled infusion in Chinese surgical patients.

BACKGROUND: Target-controlled infusion (TCI) has been recently developed and successfully implemented in clinical practice. This study was conducted to determine the pharmacokinetics of TCI administered sufentanil in Chinese surgical patients. METHODS: The pharmacokinetics of sufentanil was investigated in 12 adult patients, aged 23-76 years, scheduled for prolonged surgery under general anesthesia. Anesthetic induction was carried out with propofol, rocuronium and TCI administered sufentanil aiming for target effect-site concentration of sufentanil 4 or 6 ng/ml. Sufentanil TCI lasted for 30 minutes. Frequent arterial blood samples (1.5 ml) were drawn during and up to 24 hours after sufentanil TCI. Plasma sufentanil concentrations were measured by liquid chromatography-tandem mass spectrometry; limit of sensitivity of mass spectrometry was 5 pg/ml. The data were analyzed with the nonlinear mixed-effect model program. RESULTS: The pharmacokinetics of TCI administered sufentanil were optimally described by a three-compartment model with the following parameters: the central volume of distribution (V(1))=5.4 L, the volume of distribution at steady-state (Vdss)=195.4 L, systemic clearance (Cl(1))=1.10 L/min, and elimination half-life (t(1/2) gamma)=271.8 minutes. Both age and gender affected the pharmacokinetic parameters. The rapid distribution clearance (Cl(2)) was negatively correlated with patient age, and the volume of slowly equilibrating compartment (V(3)) was positively correlated with age. The Cl(2) and the volume of rapidly equilibrating compartment (V(2)) were influenced by gender with male patients showing higher values of Cl(2) and V(2) than female patients. There was no relationship of body weight, lean body mass, plasma albumin, or target effect-site concentration of sufentanil with any of the pharmacokinetic parameters studied. CONCLUSIONS: The pharmacokinetics of TCI administered sufentanil in Chinese patients can be adequately described by a three-compartment model. Pharmacokinetics adjusted to the individual patient should improve the accuracy of TCI systems.

Clinical evaluation of target controlled infusion system for sufentanil administration.

BACKGROUND: Sufentanil target controlled infusion (TCI) provides stable analgesia, better hemodynamic control than a bolus injection of intravenous anesthetics, anticipated recovery and improved quality of anesthesia during perioperative period. This study evaluated the accuracy and feasibility of TCI system for sufentanil at high concentrations in Chinese surgical patients. METHODS: Twelve low risk adult patients undergoing elective surgery under general anesthesia were included in this study. Sufentanil was administered with a specific TCI system incorporating the population pharmacokinetic data of sufentanil previously reported, using a target effect-site concentration of sufentanil 4 or 6 ng/ml. Sufentanil TCI duration was 30 minutes. Frequent arterial blood samples were taken during and up to 24 hours after sufentanil TCI for determination of plasma sufentanil concentrations by liquid chromatography-mass spectrometry/mass spectrometry. The changes of circulatory system function during the procedure, recovery profile and adverse effects were recorded. Measured plasma sufentanil concentrations were compared with the values predicted by the TCI system. The bias (median performance error, MDPE), precision (median absolute performance error, MDAPE) and wobble (variability of performance error) of the sufentanil TCI system were determined. RESULTS: All patients had stable cardiovascular variables during induction and maintenance of anesthesia. Time to eye opening and extubation were (5.6 + or - 1.7) minutes when TCI set to 4 ng/ml and (7.2 + or - 2.3) minutes when set to 6 ng/ml. There was no episode of agitation, muscle rigidity or intraoperative awareness. The bias (MDPE), precision (MDAPE) and wobble of the sufentanil TCI system were -3.7%, 18.9% and 19.6% respectively during TCI, and the MDPE, MDAPE and wobble were -29.1%, 31.7% and 15.0% respectively after TCI (up to 8 hours). CONCLUSIONS: The TCI system programmed for sufentanil at 4 or 6 ng/ml was considered acceptable for clinical use in low risk Chinese surgical patients. But the relatively larger MDPE and MDAPE after TCI suggest improvements of the pharmacokinetic model are needed.

A simple method for the study of salbutamol pharmacokinetics by ion chromatography with direct conductivity detection.

A simple method for the study of the pharmacokinetics of salbutamol using ion chromatography with direct conductivity detection without chemical suppression is presented in this paper. Baseline separation of salbutamol from plasma components was achieved by using diluted HNO(3) (2mmoll(-1)) as mobile phase with acetonitrile (6%, v/v) as modifier. Atenolol was utilized as internal standard. Under the optimal conditions, the linear regression coefficients of the calibration curves are 0.996 within the concentration range of 1000-3ngml(-1) salbutamol. The detection limit (signal-to-noise ratio = 3) was 1ngml(-1) salbutamol. The noncompartmental pharmacokinetic parameters for salbutamol following administration of 8mg salbutamol to 18 subjects were tested. The results coincided most satisfactorily with the results obtained by using reversed-phase high performance liquid chromatography (HPLC) with fluorescence detection.