Abstract

Cyclophospharnide (CY) is a very useful chemotherapy agent that also is used for immunosuppression due to its toxicity to mature T cells. It is perhaps the most commonly used agent in high dose chemotherapy prior to hematopoietic stem cell transplantation. Its role in this setting is primarily immune suppression, since it is minimally toxic to myeloid and lymphoid precursors. We have established that careful individual pharmacokinetic targeting of busulfan, commonly used with cyclophsophamide in the stem cell transplantation preparative regimen for its complimentary toxicity to hematopoietic progenitor cells, will avoid morbidity and mortality associated with the high dose regimen. However, control of busulfan plasma levels alone is not sufficient to prohibit regimen-related toxicity. Variability in CY pharmacokinetics and its role in the outcome of stem cell transplantation is unstudied. Cyclophsophamide itself is inactive. The cytotoxic effects of CY are mediated through cytochrome P 450-mediated conversion to hydroxycyclophosphamide (HCY). HCY is an analytical challenge since it has a half-life of only minutes in a blood sample. We have developed a chemical analysis applicable in the clinic, which traps HCY as a pair of hydrazone diasteriomers that are stable and amenable to HPLC analysis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR012609-03
Application #
6310164
Study Section
Project Start
2000-03-01
Project End
2001-02-28
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$111,316
Indirect Cost

  Institution

Name
University of Washington
Department
Type
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Telford, Dawn E; Lipson, Sara M; Barrett, P Hugh R et al. (2005) A novel inhibitor of oxidosqualene:lanosterol cyclase inhibits very low-density lipoprotein apolipoprotein B100 (apoB100) production and enhances low-density lipoprotein apoB100 catabolism through marked reduction in hepatic cholesterol content. Arterioscler Thromb Vasc Biol 25:2608-14
Dash, Ranjan K; Bell, Bradley M; Kushmerick, Martin J et al. (2005) Estimating in vitro mitochondrial oxygen consumption during muscle contraction and recovery: a novel approach that accounts for diffusion. Ann Biomed Eng 33:343-55
Dodds, Michael G; Hooker, Andrew C; Vicini, Paolo (2005) Robust population pharmacokinetic experiment design. J Pharmacokinet Pharmacodyn 32:33-64
Spilker, Mary E; Seng, Kok-Yong; Yao, Amy A et al. (2005) Mixture model approach to tumor classification based on pharmacokinetic measures of tumor permeability. J Magn Reson Imaging 22:549-58
Lukas, J C; Suarez, A M; Valverde, M P et al. (2005) Time-dependent pharmacokinetics of cyclosporine (Neoral) in de novo renal transplant patients. J Clin Pharm Ther 30:549-57
Tannock, L R; Little, P J; Tsoi, C et al. (2004) Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans. Diabetologia 47:837-43
Foracchia, Marco; Hooker, Andrew; Vicini, Paolo et al. (2004) POPED, a software for optimal experiment design in population kinetics. Comput Methods Programs Biomed 74:29-46
Welty, Francine K; Lichtenstein, Alice H; Barrett, P Hugh R et al. (2004) Interrelationships between human apolipoprotein A-I and apolipoproteins B-48 and B-100 kinetics using stable isotopes. Arterioscler Thromb Vasc Biol 24:1703-7
Calvo, R; Telletxea, S; Leal, N et al. (2004) Influence of formulation on propofol pharmacokinetics and pharmacodynamics in anesthetized patients. Acta Anaesthesiol Scand 48:1038-48
Prinsen, Berthil H C M T; Romijn, Johannes A; Bisschop, Peter H et al. (2003) Endogenous cholesterol synthesis is associated with VLDL-2 apoB-100 production in healthy humans. J Lipid Res 44:1341-8

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