Journal ArticleDOI
Clinical Pharmacology of Cyclophosphamide and Ifosfamide
TLDR
The oxazaphosphorine cyclophosphamide (CPA) and ifosfamide (IFO) are two commonly used DNA- alkylating agents in cancer chemotherapy and the pharmacokinetics and pharmacodynamics of the two important agents are highlighted.Abstract:
The oxazaphosphorine cyclophosphamide (CPA) and ifosfamide (IFO) are two commonly used DNA- alkylating agents in cancer chemotherapy. This review highlights the pharmacokinetics and pharmacodynamics of the two important agents. As alkylating agents, CPA and IFO are usually combined with other anticancer drugs in the chemotherapy of solid tumors and hematological malignancies to obtain synergistic or additive anticancer effect due to complementary mechanism of action. Both compounds are prodrugs that are activated via 4-hydroxylation by cytochrome P450s such as CYP2B6 and CYP3A4 to generate alkylating nitrogen mustards (phosphoramide mustard and ifosforamide mustard) and the byproduct acrolein. The resultant mustards can alkylate DNA to form DNA-DNA cross-links, leading to inhibition of DNA synthesis and cell apoptosis. Both CPA and IFO are also inactivated by N-dechloroethylation, resulting in N-dechloroethylated metabolites and the byproduct chloroacetaldehyde. Acrolein is the causative agent for hemorrhagic cystitis, whereas chloroacetaldehyde induces nephrotoxicity and neurotoxicity. Pharmacokinetics of CPA and IFO is markedly influenced by route of administration and duration of treatment, age, comedication, liver and renal function. Large interpatient variability in pharmacokinetics, clinical response rate and toxicity has been observed in cancer patients treated with CPA or IFO. Resistance to CPA or IFO occurs due to decreased activation by CYP3A4 and CYP2B6, increased deactivation of the agents, decreased entry into or increased efflux from tumor cells, increased cellular thiol level, increased DNA repair capacity, and/or deficient apoptotic response to DNA damage. A full understanding of factors affecting the pharmacokinetics, pharmacodynamics, toxicology and pharmacogenetics of CPA and IFO is important to optimize the dose and regimens of CPA and IFO in cancer chemotherapy.read more
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Journal ArticleDOI
Polymorphism of human cytochrome P450 enzymes and its clinical impact
TL;DR: Current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) is highlighted to understand the large interindividual variability in drug clearance and responses in clinical practice and to improve the efficacy and safety of both prospective and currently available drugs.
Journal ArticleDOI
Astaxanthin intervention ameliorates cyclophosphamide-induced oxidative stress, DNA damage and early hepatocarcinogenesis in rat: role of Nrf2, p53, p38 and phase-II enzymes.
TL;DR: Astaxanthin is a potent antioxidant and attenuates oxidative stress, DNA damage, cell death as well as induction of early hepatocarcinogenesis in rat induced by cyclophosphamide, providing the evidence that one of the mechanism of chemoprotection offered by astaxanth in is mediated through Nrf2-ARE pathway.
Journal ArticleDOI
New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2.
Giuliano Ciarimboli,Svenja K. Holle,Beate Vollenbröcker,Yohannes Hagos,Stefan Reuter,Gerhard Burckhardt,Stefan Bierer,Edwin Herrmann,Hermann Pavenstädt,Rainer Rossi,Robert Kleta,Eberhard Schlatter +11 more
TL;DR: It is proposed that the nephrotoxicity of ifosfamide is due to its selective uptake by hOCT2 into renal proximal tubular cells, and that coadministration of cimetidine may be used to prevent ifOSfamide-induced neph rotoxicity.
Journal ArticleDOI
Nephrotoxicity of anticancer treatment.
TL;DR: In routine clinical practice, monitoring of kidney function is mandatory in order to identify nephrotoxicity early, allowing dosage adjustments or withdrawal of the offending drug.
Journal ArticleDOI
Kinetics and Mechanism of Protein Tyrosine Phosphatase 1B Inactivation by Acrolein
TL;DR: Overall, the data suggest that enzyme inactivation occurs via conjugate addition of the catalytic cysteine residue to the carbon-carbon double bond of acrolein, and that inactivation of PTPs should be considered as a possible contributor to the diverse biological activities of ac rolein and structurally related alpha,beta-unsaturated aldehydes.
References
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Journal Article
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Pharmacogenomics — Drug Disposition, Drug Targets, and Side Effects
TL;DR: The existence of large population differences with small intrapatient variability is consistent with inheritance as a determinant of drug response; it is estimated that genetics can account for 20 to 95 percent of variability in drug disposition and effects.
Journal ArticleDOI
The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.
Jürgen M. Lehmann,David D. McKee,Michael A. Watson,Timothy M. Willson,John T. Moore,Steven A. Kliewer +5 more
TL;DR: The identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP 3A4 expression is reported.
Journal ArticleDOI
Mammalian ABC Transporters in Health and Disease
Piet Borst,R.P.J. Oude Elferink +1 more
TL;DR: This work focuses on three topics: ABC transporters transporting drugs (xenotoxins) and drug conjugates, and a rapidly increasing number of ABC Transporters found to play a role in lipid transport.
Journal ArticleDOI
Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense
TL;DR: The role of these four ABC transporter proteins in protecting tissues from a variety of toxicants is discussed and species variations in substrate specificity and tissue distribution of these transporters are addressed since these properties have implications for in vivo models of toxicity used for drug discovery and development.