Pharmacokinetics of N-2-chloroethylaziridine, a volatile cytotoxic metabolite of cyclophosphamide, in the rat

Cancer Chemotherapy and Pharmacology

Volumn 58, Issue 4, 2006, Pages 532-539

  Lu, Hong ^a,b   Chan, Kenneth K ^a  

^a OHIO STATE UNIVERSITY   (United States)

^b GLAXOSMITHKLINE   (United States)

Author keywords

Cyclophophamide; GC MS assay; N 2 Chloroethylaziridine; Pharmacokinetics; Phosphoramide mustard

Indexed keywords

4 HYDROXYCYCLOPHOSPHAMIDE; AZIRIDINE DERIVATIVE; CYCLOPHOSPHAMIDE; DRUG METABOLITE; N 2 CHLOROETHYLAZIRIDINE; PHOSPHORAMIDE MUSTARD; STABLE ISOTOPE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; DNA ALKYLATION; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DEGRADATION; DRUG HALF LIFE; DRUG PENETRATION; GAS CHROMATOGRAPHY; ISOTOPE DILUTION ASSAY; KIDNEY CLEARANCE; MALE; MASS SPECTROMETRY; NONHUMAN; PRIORITY JOURNAL; RAT; RAT STRAIN; URINARY EXCRETION;

ANIMALS; AREA UNDER CURVE; AZIRIDINES; GAS CHROMATOGRAPHY-MASS SPECTROMETRY; HALF-LIFE; HUMANS; MALE; METABOLIC CLEARANCE RATE; PHOSPHORAMIDE MUSTARDS; PROTEIN BINDING; RATS; RATS, SPRAGUE-DAWLEY;

EID: 33745698204     PISSN: 03445704     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00280-006-0196-7     Document Type: Article

References (22)

1. Chen CS, Jounaidi Y, Waxman DJ (2005) Enantioselective metabolism and cytotoxicity of R-ifosfamide and S-ifosfamide by tumor cell-expreesed cytochromes P450. Drug Metab Dispos 33:1261-1267
2. Philip PA, Ali-Sadat S, Doehmer J, Kocarek T, Akhtar A, Lu H, Chan KK (1999) Use of V79 cells with stably transfected cytochrome P450 cDNAs in studying the metabolism and effects of cytotoxic drugs. Cancer Chemoth Pharm 43:59-67
3. Brock N, Gross R, Hohorst HG, Klein HO, Schneider B (1971) Activation of cyclophosphamide in man and animals. Cancer 27:1512-1529
4. Hong PS, Srigritsanapol A, Chan KK (1991) Pharmacokinetics of 4-hydroxycyclophosphamide and metabolites in the rat. Drug Metab Dispos 19:1-7
5. Chan KK, Hong PS, Tutsch K, Trump DL (1994) Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508. Cancer Res 54:6421-6429
6. Ludeman SM (1999) The chemistry of the metabolites of cyclophosphamide. Curr Pharm Design 5:627-643
7. Struck RF, Kirk MC, Witt MH, Laster RW (1975) Isolation and mass spectral identification of blood metabolites of cyclophosphamide: evidence for phosphoramide mustard as the biologically active metabolite. Biomed Environ Mass Spectrom 2:46-53
8. Colvin M, Brundrett RB, Kan MN, Jardin I, Fenselau C (1976) Akylating properties of phosphoramide mustard. Cancer Res 36:1122-1126
9. Chan KK, Zheng JJ, Wang JJ, Dea P, Muggia FM (1994) Retention of cytotoxicity of phosphoramide mustard (PM) aqueous solution after its complete degradation. Proc Am Assoc Cancer Res 35:300
10. Rauen HM, Norpoth K (1968) A volatile compound N-(2-chloroethyl) aziridine in the exhaled air of rats after administration of endoxan. Klin Wochenschr 46:272-275
11. Lu H, Chan KK (1996) Gas chromatographic-mass spectrometric assay for N-2-chloroethylaziridine, a volatile cytotoxic metabolite of cyclophosphamide, in rat plasma. J Chromatogr B 678:219-225
12. Flowers JL, Ludeman SM, Gamcsik MP, Colvin OM, Shao KL, Boal JH, Springer JB, Adams DJ (2000) Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide. Cancer Chemoth Pharm 45:335-344
13. Shulman-Roskes EM, Noe DA, Gamcsik MP, Marlow AL, Hilton J, Hausheer FH, Colvin OM, Ludeman SM (1998) The partitioning of phosphoramide mustard and its aziridinium ions among alkylation and P-N bond hydrolysis reactions. J Med Chem 41:515-529
14. Chan KK, Hong SC, Watson E, Deng SK (1986) Identification of new metabolites of phosphoraramide and nornitrogen mustards and cyclophosphamide in rat urine using ion cluster techniques. Biomed Mass Spectrom 13:145-154
15. Hong PS, Chan KK (1987) Identification and quantitation of alcophosphamide, a metabolite of cyclophosphamide, in the rat using chemical ionization mass spectrometry. Biomed Mass Spectrom 14:167-172
16. Watson E, Dea P, Chan KK (1985) Kinetics of phosphoramide mustard hydrolysis in aqueous solution. J Pharm Sci 74:1283-1292
17. Hong PS, Chan KK (1989) Analysis of 4-hydroxycyclophosphamide in plasma by gas chromatography-mass spectrometry. J Chromatogr 495:131-138
18. Wang JJ, Lu H, Chan KK (2000) Stereoselective pharmacokinetics of ifosfamide in male and female rats. AAPS Pharmsci, 2 (article 17):1-11
19. Mehvar R (1991) Relationship of apparent systemic clearance to individual organ clearances: Effect of pulmonary clearance and site of drug administration and measurement. Pharm Res 8(3):306-312
20. Yuan ZM, Smith PB, Brundrett RB, Colvin OM, C. Fenselau C (1991) Glutathione conjugation with phosphoramide mustard and cyclophosphamide-a mechanistic study using tandem mass spetrometry. Drug Metab Dispos 19:625-629
21. Millis KK, Colvin ME, Shulman-Roskes EM, Ludeman SM, Colvin OM, Gamcsik MP (1995) Comparison of the protonation of isophosphoramide and phosphoramide mustard. J Med Chem 38:2166-2175
22. Hata Y, Watanabe M (1994) Metabolism of aziridines and the mechanism of their cytotoxicity. Drug Metab Rev 26:575-604