Pharmacokinetics and efficacy of ropivacaine in Chinese patients following intra-articular administration.

OBJECTIVE: The purpose of the present study was to investigate the pharmacokinetics and efficacy of ropivacaine in Chinese patients by intra-articular administration after arthroscopic knee surgery, in order to assess the safety and efficacy. PATIENTS AND METHODS: 21 ASA I-II patients received a single-dose of ropivacaine 150 mg in a 20 ml intra-articular injection at the end of surgery. Plasma samples were collected prior to and after ropivacaine administration. Plasma concentrations of ropivacaine were measured by HPLC. Pharmacokinetic parameters were calculated using noncompartmental analysis. Population pharmacokinetic modeling was performed to yield estimates of clearance, volume of distribution, and absorption rate constant. An analysis of covariates on the pharmacokinetic parameters was also carried out. Pain assessments were made using a verbal rating scale at intervals of 2, 4, 8, 12, 24, 36, 48 and 72 hours after surgery. RESULTS: The results show that the peak plasma concentrations occurred at an average of 0.93 ± 0.56 h (0.25 - 2 h), with a mean of 0.91 ± 0.4 mg/l (range 0.35 - 1.54 mg/l). The peak plasma concentrations and the times to reach the peak plasma concentration exhibited a marked variability among the subjects. All concentrations were well below the estimated toxic threshold (2.2 mg/l). No patient experienced adverse events that may have been related to ropivacaine administration. The intra-articular use of ropivacaine provided excellent control of pain after knee arthroscopy. CONCLUSION: Ropivacaine 150 mg provided satisfactory postoperative pain relief and can be safely administered by intraarticular injection in Chinese patients after arthroscopic knee surgery and the pharmacokinetic profiles of ropivacaine exhibited marked variability among the subjects. The high variability of pharmacokinetic profiles in this study may be caused by gender and body weight.

Stereoselective binding of mexiletine and ketoprofen enantiomers with human serum albumin domains.

AIM: To investigate the stereoselective binding of mexiletine or ketoprofen enantiomers with different recombinant domains of human serum albumin (HSA). METHODS: Three domains (HSA DOM I, II and III) were expressed in Pichia pastoris GS115 cells. Blue Sepharose 6 Fast Flow was employed to purify the recombinant HSA domains. The binding properties of the standard ligands, digitoxin, phenylbutazone and diazepam, and the chiral drugs to HSA domains were investigated using ultrafiltration. The concentrations of the standard ligands, ketoprofen and mexiletine were analyzed with HPLC. RESULTS: The recombinant HSA domains were highly purified as shown by SDS-PAGE and Western blotting analyses. The standard HSA ligands digitoxin, phenylbutazone and diazepam selectively binds to DOM I, DOM II and DOM III, respectively. For the chiral drugs, R-ketoprofen showed a higher binding affinity toward DOM III than S-ketoprofen, whereas S-mexiletine bound to DOM II with a greater affinity than R-mexiletine. CONCLUSION: The results demonstrate that HSA DOM III possesses the chiral recognition ability for the ketoprofen enantiomers, whereas HSA DOM II possesses that for the mexiletine enantiomers.

Analysis of flurbiprofen, ketoprofen and etodolac enantiomers by pre-column derivatization RP-HPLC and application to drug-protein binding in human plasma.

A stereoselective reversed-phase high-performance liquid chromatography (HPLC) assay to determine the enantiomers of flurbiprofen, ketoprofen and etodolac in human plasma was developed. Chiral drug enantiomers were extracted from human plasma with liquid-liquid extraction. Then flurbiprofen and ketoprofen enantiomers reacted with the acylation reagent thionyl chloride and pre-column chiral derivatization reagent (S)-(-)-alpha-(1-naphthyl)ethylamine (S-NEA), and etodolac enantiomers reacted with S-NEA using 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT) as coupling agents. The derivatized products were separated on an Agilent Zorbax C18 (4.6 mm x 250 mm, 5 microm) column with a mixture of acetonitrile-0.01 mol.L(-1) phosphate buffer (pH 4.5) (70:30, v/v) for flurbiprofen enantiomers, acetonitrile-0.01 mol.L(-1) phosphate buffer (pH 4.5) (60:40, v/v) for ketoprofen enantiomers and methonal-0.01 mol.L(-1) potassium dihydrogen phosphate buffer (pH 4.5) (88:12, v/v) for etodolac enantiomers as mobile phase. The flow of mobile phase was set at 0.8 mL.min(-1) and the detection wavelength of UV detector was set at 250 nm for flurbiprofen and ketoprofen enantiomers and 278 nm for etodolac enantiomers. The assay was linear from 0.5 to 50 microg.mL(-1) for each enantiomer. The inter- and intra-day precision (R.S.D.) was less than 10% and the average extraction recovery was more than 87% for each enantiomer. The limit of quantification for the method was 0.5 microg.mL(-1) (R.S.D.<10%, n=5). The method developed was used to study the drug-protein binding of flurbiprofen, ketoprofen and etodolac enantiomers in human plasma. The results showed that the stereoselective binding of etodolac enantiomer was observed and flurbiprofen and ketoprofen enantiomers were not.

Simultaneous determination of mandelic acid enantiomers and phenylglyoxylic acid in urine by high-performance liquid chromatography with precolumn derivatization.

A reversed-phase HPLC method for the simultaneous quantitative determination of mandelic acid enantiomers (MA) and phenylglyoxylic acid (PGA) in urine is described. MA and PGA were extracted with ethyl acetate from urine at acidic pH and derivatized with S-(-)-1-(1-naphthyl) ethylamine. A ZORBAX SB-C(18) column (250 mm x 4.6mm i.d., 5 microm, Agilent, USA) was used with a mobile phase composed of methanol-10 mmol/L phosphate buffer [pH 2.5 (65:35, v/v)] at a flow-rate of 0.8 ml/min. Detection was set at UV wavelength of 254 nm. The mean absolute recoveries were 94.2%, 91.9%, 92.5% and 86.3% for S-MA, R-MA, PGA and salicylic acid (I.S.), respectively. The intra- and inter-day precisions determined at three different concentrations ranged from 2.8% to 4.8%, 0.7% to 7.7% and 1.3% to 6.8%, respectively. The lower limits of detection for MA enantiomers and PGA in urine were 1 microg/ml and the lower limits of quantification were 5 microg/ml (R.S.D.<10%, n=5). The method has been applied to determine the urinary excretion of MA enantiomers and PGA from Sprague-Dawley rats after orally administered with styrene.

Determination of rutin deca(H-) sulfate sodium in rat plasma using ion-pairing liquid chromatography after ion-pairing solid-phase extraction.

Rutin deca(H-) sulfate sodium (RDS) is one of the most important drug candidates, which possesses very good activity as inhibitor of the complement system of warm-blooded animals and human immunodeficiency virus (HIV). In order to understand RDS metabolism and disposition, an ion-pairing coupled with solid-phase extraction technique (IP-SPE) was developed to extract RDS from rat plasma sample. Tetrabutyl ammonium bromide (TBAB) buffer (0.2 M, pH 8.0) was used as the ion-pairing extraction reagent and LC-18 was used as SPE sorbent. In addition, an ion-pairing HPLC method was established for the specific determination of RDS. A reversed phase C8 column was used for the separation of RDS and nitrendipine (internal standard). The mobile phase was composed of 10 mM phosphate buffer solution containing 25 mM TBAB-acetonitrile (52:48, v/v, pH 7.5). The calibration curve was linear from 0.3 to 30 nmol/mL. The analytical recovery from rat plasma was found to be 97.9+/-4.1% (n = 15). LOD and LOQ for RDS in plasma were calculated to be 0.12 nmol/mL and 0.30+/-0.024 nmol/mL (R.S.D. = 8.2%, n = 5), respectively. The intra- and inter-day precision was less than 9.2%. The assay was applied to a preliminary pharmacokinetic study in three male rats after those received a single intravenous bolus via caudal vein of 12 micromol/kg RDS.