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2.
J Pharm Biomed Anal ; 43(2): 784-7, 2007 Jan 17.
Article in English | MEDLINE | ID: mdl-16971082

ABSTRACT

A rapid, sensitive and selective method was developed and validated using LC/MS/MS for determination of MS-275 in human plasma. Sample preparation involved a single step liquid-liquid extraction by the addition of 0.2 ml of plasma with 5 ml acetonitrile/n-butyl-chloride. Separation of the compounds of interest, including the internal standard paclitaxel, was achieved on a Waters X-Terra C(18) (50 mm x 2.1mm i.d., 3.5 microm) analytical column using a mobile phase consisting of acetonitrile/ammonium acetate (pH 2.9; 2mM)(60:40, v/v) containing 0.1% formic acid and isocratic flow at 0.15 ml/min for 3 min. The analytes were monitored by tandem-mass spectrometry with electrospray positive ionization. Linear calibration curves were generated over the range of 0.5-100 ng/ml with values for the coefficient of determination of >0.99. The values for both within day and between day precision and accuracy were well within the generally accepted criteria for analytical methods (<15%). This method was subsequently used to measure concentrations of MS-275 in cancer patients receiving an oral weekly dose of 4 mg/m(2).


Subject(s)
Antineoplastic Agents/blood , Benzamides/blood , Chromatography, High Pressure Liquid/methods , Pyridines/blood , Spectrometry, Mass, Electrospray Ionization/methods , Tandem Mass Spectrometry/methods , Acetates/chemistry , Acetonitriles/chemistry , Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Butanes/chemistry , Calibration , Chromatography, High Pressure Liquid/standards , Drug Stability , Enzyme Inhibitors/blood , Formates/chemistry , Histone Deacetylase Inhibitors , Humans , Hydrogen-Ion Concentration , Least-Squares Analysis , Molecular Structure , Neoplasms/blood , Pyridines/pharmacology , Regression Analysis , Reproducibility of Results , Sensitivity and Specificity , Solvents/chemistry , Spectrometry, Mass, Electrospray Ionization/standards , Tandem Mass Spectrometry/standards
3.
J Clin Oncol ; 23(17): 3906-11, 2005 Jun 10.
Article in English | MEDLINE | ID: mdl-15851763

ABSTRACT

PURPOSE: To characterize the pharmacokinetic behavior of 5-azacitidine (5-AC), a cytidine nucleoside analog, when given with phenylbutyrate, a histone deaceytlase inhibitor. PATIENTS AND METHODS: Pharmacokinetic data were obtained from two trials involving patients with solid tumor and hematologic malignancies. 5-AC at doses ranging from 10 to 75 mg/m2/d was administered once daily as a subcutaneous injection for 5 to 21 days in combination with phenylbutyrate administered as a continuous intravenous infusion for varying dose and duration every 28 or 35 days. Serial plasma samples were collected up to 24 hours after 5-AC administration. 5-AC was quantitated using a validated liquid chromatograph/tandem mass spectrometry method. RESULTS: 5-AC was rapidly absorbed with the mean T(max) occurring at 0.47 hour. Average maximum concentration (C(max)) and area under the curve (AUC(0-infinity)) values increased in a dose-proportionate manner with increasing dose from 10 to 75 mg/m2/d; the mean +/- SD C(max) and AUC(0-infinity) at 10 mg/m2/d were 776 +/- 459 nM and 1,355 +/- 1,125 h*nM, respectively, and at 75 mg/m2/d were 4,871 +/- 1,398 nM and 6,582 +/- 2,560 h*nM, respectively. Despite a short terminal half-life of 1.5 +/- 2.3 hours, inhibition of DNA methyl transferase activity in tumors of patients receiving 5-AC has been documented. CONCLUSION: 5-AC is rapidly absorbed and eliminated when administered subcutaneously. Sufficient 5-AC exposure is achieved to produce pharmacodynamic effects in tumors.


Subject(s)
Antimetabolites, Antineoplastic/pharmacokinetics , Azacitidine/pharmacokinetics , Hematologic Neoplasms/metabolism , Phenylbutyrates/pharmacokinetics , Antimetabolites, Antineoplastic/administration & dosage , Azacitidine/administration & dosage , Biological Availability , Chromatography, High Pressure Liquid , Drug Administration Schedule , Drug Therapy, Combination , Hematologic Neoplasms/drug therapy , Humans , Metabolic Clearance Rate , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/metabolism , Phenylbutyrates/administration & dosage
4.
Article in English | MEDLINE | ID: mdl-15797523

ABSTRACT

A rapid, sensitive and specific method was developed and validated using liquid chromatography-tandem mass spectrometry (LC/MS/MS) for determination of gefitinib in human plasma and mouse plasma and tissue. Sample preparation involved a single protein precipitation step by the addition of 0.1 mL of plasma or a 200 mg/mL tissue homogenate diluted 1/10 in human plasma with 0.3 mL acetonitrile. Separation of the compounds of interest, including the internal standard (d8)-gefitinib, was achieved on a Waters X-Terra C18 (50 mm x 2.1 mm i.d., 3.5 microm) analytical column using a mobile phase consisting of acetonitrile-water (70:30, v/v) containing 0.1% formic acid and isocratic flow at 0.15 mL/min for 3 min. The analytes were monitored by tandem mass spectrometry with electrospray positive ionization. Linear calibration curves were generated over the range of 1-1000 ng/mL for the human plasma samples and 5-1000 ng/mL for mouse plasma and tissue samples with values for the coefficient of determination of > 0.99. The values for both within- and between-day precision and accuracy were well within the generally accepted criteria for analytical methods (< 15%). This method was subsequently used to measure concentrations of gefitinib in mice following administration of a single dose of 150 mg/kg intraperitoneally and in cancer patients receiving an oral daily dose of 250 mg.


Subject(s)
Chromatography, High Pressure Liquid/methods , ErbB Receptors/antagonists & inhibitors , Mass Spectrometry/methods , Quinazolines/blood , Animals , Biliary Tract Neoplasms/chemistry , Drug Stability , Female , Gefitinib , Humans , Liver/chemistry , Mice , Mice, Nude , Neoplasm Transplantation , Quinazolines/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Skin/chemistry
5.
J Pharm Biomed Anal ; 37(4): 751-6, 2005 Apr 01.
Article in English | MEDLINE | ID: mdl-15797797

ABSTRACT

COL-3, 6-deoxy-6-desmethyl-4-desdimethylamino-tetracycline, is a matrix metalloproteinase inhibitor currently in clinical development. A HPLC-UV method to quantitate COL-3 in human plasma was developed. COL-3 was extracted from plasma using solid-phase extraction cartridges. COL-3 is separated on a Waters Symmetry Shield RP8 (3.9 mm x150 mm, 5 microm) column with EDTA (0.001 M) in sodium acetate (0.01 M, pH 3.5)-acetonitrile mobile phase using a gradient profile at a flow rate of 1 ml/min for 22 min. Carryover was eliminated by using an extended needle wash of methanol:acetonitrile:dichloromethane (1:1:1, v/v/v). Detection of COL-3 and the internal standard, chrysin, was observed at 350 nm. COL-3 and chrysin elute at 8.9 and 9.9 min, respectively. The lower limit of quantitation in human plasma of COL-3 was 75 ng/ml, linearity was observed from 75 to 10,000 ng/ml. A 30,000 ng/ml sample that was diluted 1:50 with plasma was accurately quantitated. This method is rapid, widely applicable, and suitable for quantifying COL-3 in patient samples enabling further clinical pharmacology characterization of COL-3.


Subject(s)
Tetracyclines/blood , Analysis of Variance , Calibration , Chromatography, High Pressure Liquid , Drug Stability , Drug Storage , Humans , Indicators and Reagents , Quality Control , Reference Standards , Spectrophotometry, Ultraviolet , Tetracyclines/analysis
6.
Article in English | MEDLINE | ID: mdl-15556519

ABSTRACT

5-Azacytidine (5AC), a nucleoside analogue and hypomethylating agent, has anticancer properties and has been utilized in the treatment of various malignancies. 5AC is unstable and rapidly hydrolyzed to several by-products, including 5-azacytosine and 5-azauracil. A sensitive, reliable method was developed to quantitate 5AC using LC/MS/MS to perform pharmacokinetic and pharmacodynamic studies on 5AC combination therapy trials. Blood samples were collected in a heparinized tube and immediately processed for storage. To increase the stability of 5AC in plasma, 25 ng/mL tetrahydrouridine was added to the plasma and snap frozen. Plasma samples were extracted using acetonitrile then cleaned up by Oasis MCX ion exchange solid-phase extraction cartridges. 5AC was separated on an YMC Jsphr M80 C(18) column with gradient elution of ammonium acetate (2 mM) with 0.1% formic acid and methanol mobile phase. 5AC elutes at 5.0 +/- 0.2 min with a total run time of 30 min. Identification was through positive-ion mode and multiple reaction monitoring mode at m/z+ 244.9-->113.0 for 5AC and m/z+ 242.0-->126.0 for 5-methyl-2'-deoxycytidine, the internal standard. The lower limit of quantitation of 5AC was 5 ng/mL in human plasma, and linearity was observed from 5 to 500 ng/mL fitted by linear regression with 1/x weight. This method is 50 times more sensitive than previously published assays and successfully allows studies to characterize the pharmacokinetics and pharmacodynamics of 5AC.


Subject(s)
Antineoplastic Agents/blood , Azacitidine/blood , Chromatography, High Pressure Liquid/methods , Spectrometry, Mass, Electrospray Ionization/methods , Antineoplastic Agents/pharmacokinetics , Azacitidine/pharmacokinetics , Calibration , Humans , Reference Standards , Sensitivity and Specificity
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