Metabolism and transport of oxazphosphorines and the clinical implications

Zhang, Jing, Tian, Quan, Chan, Sui Yung, Li, Shu Chuen, Zhou, Shufeng, Duan, Wei and Zhu, Yi-Zhun 2005, Metabolism and transport of oxazphosphorines and the clinical implications, Drug metabolism reviews, vol. 37, no. 4, pp. 611-703.

Attached Files
Name Description MIMEType Size Downloads

Title Metabolism and transport of oxazphosphorines and the clinical implications
Author(s) Zhang, Jing
Tian, Quan
Chan, Sui Yung
Li, Shu Chuen
Zhou, Shufeng
Duan, Wei
Zhu, Yi-Zhun
Journal name Drug metabolism reviews
Volume number 37
Issue number 4
Start page 611
End page 703
Publisher Informa Healthcare
Place of publication New York, N.Y.
Publication date 2005-07
ISSN 0360-2532
1097-9883
Keyword(s) oxazaphosphorine
cyclophosphamide
ifosfamide
metabolism
transport
cytochrome P450
pharmacokinetics
toxicity
resistance
Summary The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO), and trofosfamide represent an important group of therapeutic agents due to their substantial antitumor and immuno-modulating activity. CPA is widely used as an anticancer drug, an immunosuppressant, and for the mobilization of hematopoetic progenitor cells from the bone marrow into peripheral blood prior to bone marrow transplantation for aplastic anemia, leukemia, and other malignancies. New oxazaphosphorines derivatives have been developed in an attempt to improve selectivity and response with reduced toxicity. These derivatives include mafosfamide (NSC 345842), glufosfamide (D19575, β-D-glucosylisophosphoramide mustard), NSC 612567 (aldophosphamide perhydrothiazine), and NSC 613060 (aldophosphamide thiazolidine). This review highlights the metabolism and transport of these oxazaphosphorines (mainly CPA and IFO, as these two oxazaphosphorine drugs are the most widely used alkylating agents) and the clinical implications. Both CPA and IFO are prodrugs that require activation by hepatic cytochrome P450 (CYP)-catalyzed 4-hydroxylation, yielding cytotoxic nitrogen mustards capable of reacting with DNA molecules to form crosslinks and lead to cell apoptosis and/or necrosis. Such prodrug activation can be enhanced within tumor cells by the CYP-based gene directed-enzyme prodrug therapy (GDEPT) approach. However, those newly synthesized oxazaphosphorine derivatives such as glufosfamide, NSC 612567 and NSC 613060, do not need hepatic activation. They are activated through other enzymatic and/or non-enzymatic pathways. For example, both NSC 612567 and NSC 613060 can be activated by plain phosphodiesterase (PDEs) in plasma and other tissues or by the high-affinity nuclear 3'-5' exonucleases associated with DNA polymerases, such as DNA polymerases and ε. The alternative CYP-catalyzed inactivation pathway by N-dechloroethylation generates the neurotoxic and nephrotoxic byproduct chloroacetaldehyde (CAA). Various aldehyde dehydrogenases (ALDHs) and glutathione S-transferases (GSTs) are involved in the detoxification of oxazaphosphorine metabolites. The metabolism of oxazaphosphorines is auto-inducible, with the activation of the orphan nuclear receptor pregnane X receptor (PXR) being the major mechanism. Oxazaphosphorine metabolism is affected by a number of factors associated with the drugs (e.g., dosage, route of administration, chirality, and drug combination) and patients (e.g., age, gender, renal and hepatic function). Several drug transporters, such as breast cancer resistance protein (BCRP), multidrug resistance associated proteins (MRP1, MRP2, and MRP4) are involved in the active uptake and efflux of parental oxazaphosphorines, their cytotoxic mustards and conjugates in hepatocytes and tumor cells. Oxazaphosphorine metabolism and transport have a major impact on pharmacokinetic variability, pharmacokinetic-pharmacodynamic relationship, toxicity, resistance, and drug interactions since the drug-metabolizing enzymes and drug transporters involved are key determinants of the pharmacokinetics and pharmacodynamics of oxazaphosphorines. A better understanding of the factors that affect the metabolism and transport of oxazaphosphorines is important for their optional use in cancer chemotherapy.
Language eng
Field of Research 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2005, Taylor & Francis Inc.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30009145

Document type: Journal Article
Collection: School of Medicine
Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 84 times in TR Web of Science
Scopus Citation Count Cited 91 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 437 Abstract Views, 0 File Downloads  -  Detailed Statistics
Created: Mon, 13 Oct 2008, 15:52:26 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.