Clinical Pharmacology of Cyclophosphamide and Ifosfamide

Abstract

The oxazaphosphorine cyclophosphamide (CPA) and ifosfamide (IFO) are two commonly used DNAalkylating 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.

Modulation of cyclophosphamide-induced early lung injury by allicin

“…CP is one of the most effective chemotherapeutic agents used in the treatment of cancers of breast (Levine et al, 2005;Hirano et al, 2008), lung (Sundstrom et al, 2005;Zhang et al, 2006), prostate (Nicolini et al, 2004), ovary (Donato et al, 2004), leukemia (Rao et al, 2005), lymphomas and non-Hodgkin's lymphoma. Significantly different from the CP-treated group using one-way ANOVA followed by the Tukey-Kramer multiple comparisons test (p50.05).…”

Protective effect of thymoquinone against cyclophosphamide-induced genotoxic damage in human lymphocytes

“…Some researchers suggested that CP generates active metabolites, like 4-hydroxycyclophosphamide, phosphoramide mustard and acrolein. These metabolites preferably alkylate N 7 position of the guanine residue of DNA and this leads to inter-and intra-strand cross-links, DNA strand breaks, cessation of DNA synthesis, DNA-protein cross-links and DNA adduct formation (15). There are a lot of studies on genotoxicity of CP.…”

Hesperidin Inhibits Cyclophosphamide-Induced Tumor Growth Delay in Mice

“…CP is activated by hepatic cytochrome P450 (CYP) isoenzymes, to form 4-hydroxycyclophosphamide, which enters the blood and is transported to tumor cells by erythrocytes. 1 Because CP is activated by CYP-catalyzed metabolites, drug interactions could modulate the pharmacokinetics by inhibition of a relevant CYP. 1 Hesperidin has been shown to significantly affect the pharmacokinetics of several drugs, such as diltiazem and verapamil, by inhibition of CYP isoenzymes.…”

“…1 Because CP is activated by CYP-catalyzed metabolites, drug interactions could modulate the pharmacokinetics by inhibition of a relevant CYP. 1 Hesperidin has been shown to significantly affect the pharmacokinetics of several drugs, such as diltiazem and verapamil, by inhibition of CYP isoenzymes. 12-15 P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrugresistant protein 1 is a glycoprotein that in humans has several families.…”

“…Cyclophosphamide (CP), one of the most widely drugs in chemotherapy, is a cytotoxic alkylating drug with a high therapeutic index and is effective against a variety of cancers. 1 Although CP is effective for the treatment of cancer, it induces a wide range of adverse side effects and toxicity, such as nausea, vomiting, and hematopoietic toxicity, that restrict the use of this drug in clinic. 1 Therefore, it is necessary to search for compounds that can reduce the harmful side effects of anticancer drugs in normal tissues.…”