Analysis of Antineoplastic Drugs

The most widely monitored neoplastic drug is methotrexate, and commercially available immunoassays are usually used for routine TDM of methotrexate in clinical laboratories. However, trace level of this drug cannot be detected using immunoassays because of sensitivity issues. Truci et al. described an HPLC-tandem mass spectro-metric technique for determination of trace amount of methotrexate in human urine of hospital personnel exposed to this neoplastic agent. After solid phase extraction, HPLC analysis was carried out using an octadecyl silica SPE column (54). Concentrations of methotrexate along with its metabolite 7-hydroxy methotrexate can be determined using HPLC. HPLC methods are also available for TDM of other antineoplastic drugs including doxorubicin, etoposide, 5-fluorouracil, mitoxantrone, mensa and demensa, taxol, aminoglutethimide, tamoxifen, and acrolein. GC with a capillary column can be used for analysis of cyclophosphamide, lomustine, and carmustine (55).

Using chlorouracil as the internal standard, Maring et al. (56) developed an HPLC method for the determination of concentration of 5-fluorouracil as well as the concentration of its metabolite 5,6-dihydrofluorouracil in plasma using a reversed-phase C18 column and UV diode array detector. Schoemaker et al. developed an HPLC protocol for simultaneous measurement of anticancer drug irinotecan (CPT-11) and its active metabolite SN-38 in human plasma after converting both CPT-11 and SN-38 to their carboxylate form by using 0.01 mol/L of sodium tetraborate. HPLC separation was achieved using a Zorbax SB-C18 column and detector used was a fluorescence detector. The detection limit was 5.0ng/mL for CPT-11 and 0.5 ng/mL for SN-38 (57). Determination of docetaxel and paclitaxel concentrations using HPLC with UV detection has also been reported after liquid-liquid extraction of these antineoplastic agents from human plasma (58). Quantification of imatinib, a selective tyrosine kinase inhibitor, in human plasma using HPLC combined with tandem mass spectrometry has been reported. The authors used a reversed-phase C18 column with a gradient of acetonitrile-ammonium formate buffer (4mmol/L at pH 4.0) for HPLC analysis. Imatinib was detected by electrospray ionization mass spectrometry with multiple-reaction monitoring mode (59). Fogil et al. described a method for determination of daunorubicin, idarubicin, doxorubicin, epirubicin, and their 13-dihydro metabolites in human plasma using HPLC and spectrofluorometric detection of all these anthracy-clines using excitation and emission wavelength of 480 and 560 nm, respectively. After extraction of these drugs from human plasma, HPLC analysis was carried out using a Supelcosil LC-CN (25 cm x 4.6 mm ID, particle size 5 ^m, Supelco Bellefonte, PA) column (60). Concentrations of these anthracyclines in human serum can also be determined using liquid chromatography combined with electrospray mass spectrometry. Lachatre et al. determined concentrations of epirubicin, doxorubicin, daunorubicin, idarubicin, and active metabolites (doxorubicinol, daunorubicinol, and idarubicinol) in human plasma using aclarubicin as the internal standard. After solid phase extractions, these drugs were analyzed using a reversed-phase C18 column (61).

GC combined with nitrogen phosphorus detector or mass spectrometry can also be used for determination of specific neoplastic drugs. Kerbusch et al. determined concentration of ifosfamide, 2- and 3-dechloroethylifosfamide in human plasma by using gas chromatography coupled with nitrogen phosphorus detector or mass spectrometry without any derivatization. Sample preparation involved liquid-liquid extraction with ethyl acetate after adding trofosfamide as the internal standard and making the serum alkaline. The authors concluded that gas chromatography with nitrogen phosphorus detector was more sensitive for analysis of these compounds compared with gas chromatography combined with positive ion electron-impact ion trap mass spectrometry (62).

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