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Dafang Zhong

Publications and source records attributed to Dafang Zhong.

At least 37 records · Page 2Linked to original sources
PubMed2005

Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans.

CYP2C9 is an important member of the cytochrome P450 enzyme superfamily with some 12 CYP2C9 alleles (*1-*12) being previously reported. Recently, we identified a new CYP2C9 allele with a Leu90Pro mutation in a Chinese poor metabolizer of lornoxicam [Si D, Guo Y, Zhang Y, Yang L, Zhou H, and Zhong D (2004) Pharmacogenetics 14:465-469]. The new allele, designated CYP2C9*13, was found to occur in approximately 2% of the Chinese population. To examine enzymatic activity of the CYP2C9*13 allele, kinetic parameters for lornoxicam 5'-hydroxylation were determined in COS-7 cells transiently transfected with pcDNA3.1 plasmids carrying wild-type CYP2C9*1, variant CYP2C9*3, and CYP2C9*13 cDNA. The protein levels of cDNA-expressed CYP2C9*3 and *13 in postmitochondrial supernatant (S9) from transfected cells were lower than those from wild-type CYP2C9*1. Mean values of Km and Vmax for CYP2C9*1, *3, and *13 were 1.24, 1.61, and 2.79 microM and 0.83, 0.28, and 0.22 pmol/min/pmol, respectively. Intrinsic clearance values (Vmax/Km) for variant CYP2C9*3 and CYP2C9*13 on the basis of CYP2C9 protein levels were separately decreased to 28% and 12% compared with wild type. In a subsequent clinical study, the AUC of lornoxicam was increased by 1.9-fold and its oral clearance (CL/F) decreased by 44% in three CYP2C9*1/*13 subjects, compared with CYP2C9*1/*1 individuals. This suggests that the CYP2C9*13 allele is associated with decreased enzymatic activity both in vitro and in vivo.

Alleles↗
PubMed2005

Liquid chromatography/tandem mass spectrometry for pharmacokinetic studies of 20(R)-ginsenoside Rg3 in dog.

A sensitive and specific liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for the investigation of the pharmacokinetics of 20(R)-ginsenoside Rg3 in dog. The plasma samples were pretreated by liquid-liquid extraction and analyzed using LC/MS/MS with an electrospray ionization interface. Dioscin was used as the internal standard. The method had a lower limit of quantitation of 0.5 ng/mL for Rg3 in 200 microL of plasma or 2 ng/mL in 100 microL of plasma, which offered a satisfactory sensitivity for the determination of Rg3 in plasma. The intra- and inter-day precisions were measured to be below 8% and accuracy between -1.5 and 1.4% for all quality control samples. This quantitation method was successfully applied to pharmacokinetic studies of Rg3 after both an oral and an intravenous administration to beagle dogs. No Rh2 and protopanaxadiol were detected in plasma.

Administration, Oral↗
PubMed2005

Determination of glufosfamide in rat plasma by liquid chromatography/tandem mass spectrometry.

A sensitive and selective high-performance analytical method based on liquid chromatography with tandem mass spectrometric detection (LC/MS/MS) was developed for the quantification of glufosfamide in rat plasma. Zidovudine was employed as internal standard. Glufosfamide was determined after methanol-mediated plasma protein precipitation using LC/MS/MS with an electrospray ionization interface in negative ion mode. Two sets of standard curves were developed, from 0.005 to 1.0 microg/mL and from 1.0 to 50.0 microg/mL. The assay was accurate (% deviations from nominal concentrations < 5%), precise and reproducible (intra- and inter-day coefficients of variation < 10%). Glufosfamide in rat plasma was stable over three freeze/thaw cycles, and at ambient temperatures, for at least 2 h. The validated method was successfully applied to the determination of glufosfamide plasma concentrations in rats for 24 h following an intravenous administration of 25 mg/kg.

Alkylating Agents↗
PubMed2005

Development and validation of a liquid chromatography/tandem mass spectrometry procedure for the quantification of adefovir in human plasma.

To investigate the pharmacokinetics of adefovir as an anti-hepatitis B virus drug, a sensitive and specific liquid chromatography/tandem mass spectrometry method was developed and validated. After a simple protein precipitation using methanol, the post-treatment samples were analyzed on a C(18) column interfaced with a triple-quadrupole tandem mass spectrometer using positive electrospray ionization. A structural analogue, PMPA, was used as the internal standard. The method was linear in the concentration range 0.25-100 ng/mL. The lower limit of quantification was 0.25 ng/mL. The intra- and inter-day relative standard deviation over the entire concentration range was 5.7% or less. The accuracy determined at three concentrations (0.75, 10 and 80 ng/mL for adefovir) was within +/-2.5% relative error. The method described here was successfully applied for the evaluation of pharmacokinetic profiles of adefovir after single oral administration doses of 5, 10 and 20 mg adefovir dipivoxil to ten healthy volunteers.

Adenine↗
PubMed2005

A liquid chromatography/tandem mass spectrometry method for the simultaneous quantification of isoniazid and ethambutol in human plasma.

Isoniazid and ethambutol are commonly used in various combination treatments for tuberculosis, and for this reason a rapid and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated for simultaneous quantification of these two drugs in human plasma. After a simple protein precipitation using methanol, the analytes and the internal standard metformin were chromatographed on a C18 column and detected by MS/MS. An atmospheric pressure chemical ionization interface was chosen to reduce ion suppression from sample matrix components and provide high sensitivity. The LC retention times for isoniazid and ethambutol were 2.46 and 2.27 min, respectively. The method was linear in the concentration range of 10.0-5000 ng/mL for each analyte using 100 microL plasma. The intra- and inter-day precisions, expressed as the relative standard deviation (RSD), were less than 5.7 and 6.4%, determined from QC samples for isoniazid and ethambutol, and the accuracies were within +/-2.1% and +/-4.5% in terms of relative error, respectively. The method was successfully employed in a pharmacokinetic study after oral administration of a multicomponent formulation containing 150 mg isoniazid, 500 mg ethambutol, 150 mg rifampicin and 250 mg pyrazinamide.

Administration, Oral↗
PubMed2005

Lornoxicam pharmacokinetics in relation to cytochrome P450 2C9 genotype.

AIMS: To investigate the pharmacokinetics of lornoxicam and the relationship with CYP2C9 polymorphism in healthy Chinese subjects. METHODS: A single oral dose of 8 mg lornoxicam was administered to 18 healthy Chinese male subjects. Plasma was sampled for 24 h post dose, and plasma concentrations of lornoxicam were measured using a validated LC/MS/MS method. CYP2C9 genotype was determined by polymerase chain reaction-based restriction fragment length polymorphism or by direct sequencing of the coding region of the CYP2C9 gene. RESULTS: Of the 18 subjects, one subject was found to be a very poor metabolizer of lornoxicam with a long t(1/2) of 106 h, a low CL/F of 0.71 ml min(-1), and a high AUC(0-infinity) of 187.6 microg ml(-1) h. Genotyping studies revealed that this subject was heterozygous for CYP2C9*3 and a new variant CYP2C9 allele. Of the other 17 subjects, 13 were *1/*1 carriers, three were *1/*3 carriers, and one was a *1/*2 carrier. Mean AUC(0-infinity) values (95% confidence intervals) of lornoxicam were 9.25 (6.55, 11.95) vs. 4.75 (3.55, 5.95) microg ml(-1) h in *1 heterozygotes vs.*1 homozygotes, and mean CL/F values were 14.8 (10.2, 19.4) vs. 32.9 (24.5, 41.3) ml min(-1), respectively (P < 0.05 for both AUC and CL/F). CONCLUSIONS: The results show that the pharmacokinetics of lornoxicam are dependent on CYP2C9 polymorphism. In particular, the presence of the CYP2C9*3 allele impairs the oral clearance of lornoxicam.

Adult↗
PubMed2005

Metabolism of pantoprazole involving conjugation with glutathione in rats.

We have investigated the metabolism of pantoprazole and have provided an explanation for the formation mechanism of its metabolites. Metabolites found in the urine of rats after oral administration of pantoprazole sodium (25 mg kg(-1)) were analysed by liquid chromatography/ion trap mass spectrometry (LC/MS(n)). The N -acetylcysteine derivatives of benzimidazole (M1) and pyridine (M2), four pyridine-related metabolites (M3-M6), and three benzimidazole-related metabolites (M7-M9) were found, none of which had been reported previously. Five of the metabolites (M1, M2, M3, M7, and M8) were isolated from the urine of rats after oral administration of pantoprazole sodium by semipreparative HPLC. Structures of these metabolites were identified by a combination analysis of LC/MS(n) and (1)H NMR spectra. Structures of the remaining four metabolites (M4, M5, M6, and M9) were tentatively assigned through LC/MS(n). The metabolites M2, M3, M4, M5 and M6 and the other metabolites (M1, M7, M8, and M9) reflected the fate of the pyridine moiety and the benzimidazole moiety, respectively. The proposed formation route of M3-M6 was via initial reduction to mercaptopyridine followed by S-methylation, O-demethylation, and S-oxidation to the corresponding sulfoxide or sulfone. Meanwhile, M8 and M9 were formed via initial reduction to the 5-difluoromethoxy-1H benzoimidazole-2-thiol (M7) followed by hydroxylation and S-methylation. The metabolism of pantoprazole included an attack by glutathione on the benzimidazole-2-carbon and pyridine-7'-carbon. It is an important metabolic pathway of pantoprazole in rats.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Interaction of baicalin and baicalein with antibiotics in the gastrointestinal tract.

To clarify the absorption mechanism of baicalin and to investigate the interaction between baicalin and antibiotics, the pharmacokinetics of baicalin and its aglycone baicalein in normal rats and in antibiotic-treated (with a mixture of neomycin and streptomycin) rats were investigated. A method of liquid chromatography-tandem mass spectrometry with a selected reaction monitoring mode was used to determine the plasma concentrations of baicalin and baicalein. The plasma concentration of total baicalein was determined after treatment of beta-glucuronidase/sulfatase. Unpaired Student's t-test was used for statistical comparison. After oral administration of baicalin, the absolute bioavailability of baicalin, based on the AUC of the baicalin parent form, was 2.2+/-0.2% in normal rats, which decreased to 1.5+/-0.2% in antibiotic-treated rats. Based on the AUC of total baicalein after enzymatic hydrolysis, the absorption of baicalin was 28.0+/-5.7%, which significantly decreased to 7.7+/-1.2% in antibiotic-treated rats. After oral administration of baicalein, the glucuronides/sulfates of baicalein were predominant in plasma. Based on the AUC of total baicalein after enzymatic hydrolysis, the absorption of baicalein was 36.1+/-4.4% in normal rats, which did not differ markedly from that in antibiotic-treated rats (P>0.05). The presence of baicalin isomer in plasma after oral administration of baicalin indicated that baicalin was transformed, at least in part, to baicalein before absorption, then to its conjugated metabolites in rats. Aminoglycosides decreased the absorption of baicalin, but not of baicalein, which indicated that antibiotics decreased the decomposition of baicalin to baicalein by inhibiting intestinal flora, and further influenced the absorption, metabolism and efficacy of baicalin. These interactions should be paid attention to in clinical studies when baicalin is administered in combination with antibiotics.

Administration, Oral↗
PubMed2005

Validated liquid chromatography-tandem mass spectrometric method for the quantitative determination of daidzein and its main metabolite daidzein glucuronide in rat plasma.

A highly selective and sensitive liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method was developed and validated to determine daidzein and its main metabolite daidzein glucuronide in rat plasma. The analytes and internal standard genistein were extracted from plasma samples by n-hexane-diethyl ether (1:4, v/v), and separated on a C18 column. The mobile phase consisted of acetonitrile-water-formic acid (80 : 20: 1, v/v/v). Detection was performed on a triple quadrupole tandem mass spectrometer by selected reaction monitoring (SRM) mode via atmospheric pressure chemical ionization (APCI) source. The method has a limit of quantification of 0.24 ng/ml. The linear calibration curves were obtained in the concentration range of 0.24-1000 ng/ml. The intra- and inter-day precisions were lower than 13.2% in terms of % RSD. The accuracy ranged from -0.5% to 2.4% in terms of % RE (relative error). This method was successfully applied to the determination of plasma concentration of daidzein and its main metabolite daidzein glucuronide in rats after an oral administration of 20 mg/kg daidzein.

Animals↗
PubMed2004

Simultaneous determination of enalapril and enalaprilat in human plasma by liquid chromatography-tandem mass spectrometry.

A rapid, sensitive, and highly selective liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of enalapril and its major active metabolite enalaprilat in human plasma. The analytes were extracted from plasma samples by liquid-liquid extraction, separated on a Zorbax Extend-C(18) column, and detected by tandem mass spectrometry with a Turbo IonSpray ionization interface. The method has a lower limit of quantification (LLOQ) of 0.1 ng/ml for both enalapril and enalaprilat. The chromatographic run time was approximately 3.5 min. The standard calibration curves for both enalapril and enalaprilat were linear in the concentration ranges of 0.10-100.0 ng/ml in human plasma. The intra- and inter-run precisions, expressed as the relative standard deviation (R.S.D.), were less than 7.7 and 7.8%, determined from QC samples for enalapril and enalaprilat, and accuracy was within +/-3.9 and +/-2.7% in terms of relative error, respectively. The method was successfully applied for the evaluation of the pharmacokinetics of enalapril and enalaprilat in 20 volunteers after an oral dose of 10 mg enalapril maleate.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Acid catalysed degradation of some spiramycin derivatives found in the antibiotic bitespiramycin.

Bitespiramycin is a novel antibiotic containing a number of 4''-acylated spiramycin derivatives (isovalerylspiramycins I-III, butanoylspiramycin III, propanoylspiramycin III and acetylspiramycin III) as major components. These spiramycin derivatives are susceptible to degradation in acid solution. Liquid chromatography-ion trap mass spectrometry (LC/MS(n)) was used to study the degradation of these spiramycin derivatives in simulated gastric fluid at 37 degrees C. All derivatives degraded by first-order reactions for which rate constants (k) and half-lives (t(1/2)) were calculated. Acyl groups at position 3 had less effect on acid-stability of spiramycin derivatives than acyl groups at position 4''. The introduction of 4''-acyl groups enhanced the acid-stability of spiramycin derivatives and altered the degradation pathway in simulated gastric fluid such that loss of forosamine rather than loss of mycarose becomes the major degradation pathway.

Anti-Bacterial Agents↗
PubMed2004

Simultaneous determination of albendazole and its major active metabolite in human plasma using a sensitive and specific liquid chromatographic-tandem mass spectrometric method.

A method for the simultaneous determination of albendazole (ABZ) and its major active metabolite albendazole sulfoxide (ABZ-SO) was developed and validated. The analytes were extracted from plasma samples by liquid-liquid extraction and analyzed using liquid chromatography-tandem mass spectrometry with an electrospray ionization interface. Estazolam was used as the internal standard. The assay was linear in the concentration range 0.4-200 ng/ml for ABZ and 4.0-2000 ng/ml for ABZ-SO. The intra- and inter-run precision (R.S.D.), calculated from quality control (QC) samples was less than 7.1 and 9.4% for ABZ and ABZ-SO, respectively. The accuracy as determined from QC samples was within +/- 3% for the analytes. Recoveries of ABZ and ABZ-SO were greater than 77 and 53%, respectively, over the calibration curve range. The method developed was successfully applied to pharmacokinetic studies of ABZ and ABZ-SO after an oral dose of 400 mg albendazole to healthy volunteers.

Albendazole↗
PubMed2004

Determination of nimodipine in human plasma by a sensitive and selective liquid chromatography-tandem mass spectrometry method.

A sensitive and highly selective liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed to determine nimodipine in human plasma. The analyte and internal standard nitrendipine were extracted from plasma samples by n-hexane-dichloromethane-isopropanol (300:150:4, v/v/v), and chromatographed on a C(18) column. The mobile phase consisted of methanol-water-formic acid (80:20:1, v/v/v). Detection was performed on a triple quadrupole tandem mass spectrometer by selected reaction monitoring (SRM) mode via atmospheric pressure chemical ionization (APCI) source. The method has a limit of quantification of 0.24 ng/ml. The linear calibration curves were obtained in the concentration range of 0.24-80 ng/ml. The intra- and inter-day precisions were lower than 4.4% in terms of relative standard deviation (R.S.D.), and the accuracy ranged from 0.0 to 5.8% in terms of relative error (RE). This validated method was successfully applied for the evaluation of pharmacokinetic profiles of nimodipine tablets administered to 18 healthy volunteers.

Adult↗
PubMed2004

Rapid determination of metformin in human plasma by liquid chromatography-tandem mass spectrometry method.

A rapid, sensitive and specific liquid chromatography-tandem mass spectrometry method is described for quantitation of metformin in human plasma. After a simple, one-step protein precipitation using acetonitrile, metformin and the internal standard diphenhydramine were chromatographed on a C(8) column and detected by tandem mass spectrometry. An atmospheric pressure chemical ionization interface was chosen to reduce ion suppression from sample matrix components and provide high sensitivity. The method has a chromatographic total run time of 3.4 min and was linear within the range 2-2000 ng/ml. Intra- and inter-day precision, expressed as the relative standard deviation (R.S.D.), ranged from 4.4 to 5.7% and from 1.3 to 2.8%, respectively. Assay accuracy was less than 1% in terms of %RE (relative error). The assay was used to evaluate the pharmacokinetics of metformin after an oral administration of multicomponent formulation containing 500 mg metformin and 2.5 mg glyburide to 20 healthy volunteers.

Gas Chromatography-Mass Spectrometry↗
PubMed2004

Simultaneous determination of chlorpheniramine and pseudoephedrine in human plasma by liquid chromatography-tandem mass spectrometry.

A sensitive and specific procedure for simultaneous quantitation of chlorpheniramine and pseudoephedrine in human plasma has been developed and validated. Analytes were extracted from plasma samples by liquid-liquid extraction, separated on a Diamonsil C18 column (250 x 4.6 mm i.d.) and detected by tandem mass spectrometry with an atmospheric pressure chemical ionization interface. Diphenhydramine was used as the internal standard. The method has a lower limit of quantitation of 0.2 and 2.0 ng/mL for chlorpheniramine and pseudoephedrine, respectively. The intra- and inter-day relative standard deviation, calculated from quality control (QC) samples were below 4.3% for chlorpheniramine and below 9.5% for pseudoephedrine. The inter-day relative error as determined from QC samples was within 4.7% for each analyte. The overall extraction recoveries of chlorpheniramine and pseudoephedrine were 77 and 61% on average, respectively. The method was successfully applied to pharmaockinetic study of chlorpheniramine and pseudoephedrine in volunteers receiving formulations containing 4 mg of chlorpheniramine maleate and 60 mg of pseudoephedrine hydrochloride.

Anti-Allergic Agents↗
PubMed2004

Study on the bioavailability of nateglinide-hydroxypropyl-beta-cyclodextrin complex capsule in rabbits by liquid chromatographic-tandem mass spectrometry.

To evaluate the bioavailability of nateglinide-hydroxypropyl-beta-cyclodextrin (HPCD) complex, a rapid and specific liquid chromatographic-tandem mass spectrometric method was developed and validated to determine nateglinide in rabbit serum. The analyte was extracted from serum samples by liquid-liquid extraction, separated on a Zorbax C(18) column and detected by tandem mass spectrometry with an atmospheric pressure chemical ionization interface. Daidzein was used as the internal standard. The method has a lower limit of quantitation of 0.25 mg/L using 200 micro L serum. The intra- and inter-day relative standard deviations calculated from quality control (QC) samples were below 4%. The inter-day relative error was within 1%. Nateglinide serum concentrations in rabbits given nateglinide-hydroxypropyl-beta-cyclodextrin complex were much higher than those given the free drug. Significant difference was observed in main pharmacokinetic parameters of t(max) and C(max) but not AUC(0-t) between the complex and free drug. It was concluded that the absorption rate of nateglinide-HPCD complex was enhanced, compared with that of nateglinide free drug.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2004

Rearrangement process occurring in the fragmentation of adefovir derivatives.

The fragmentation of the antiviral drug adefovir dipivoxil and its two active metabolites, adefovir and monopivoxil adefovir, was investigated using both ion trap and triple-quadrupole mass spectrometers. Fragment ions due to loss of 30 Da were observed and attributed to an unanticipated rearrangement process by loss of formaldehyde. The proposed mechanism is supported with the aid of three newly synthesized adefovir derivatives and with accurate mass measurement. Other fragmentations by loss of a pivaloyl group, loss of water, C-P bond cleavage and C-O bond cleavage were also observed for adefovir derivatives. It was concluded that the compounds containing a >POO-CHR-OCO- group generally displayed a rearrangement reaction by loss of RCHO in collision-induced dissociation, and the process generally required an activation energy lower than for a direct bond cleavage.

Adenine↗