The effect of chloramphenicol and sulphaphenazole on the biotransformation of cyclophosphamide in man.

Faber, O.; Mouridsen, H. T.; Skovsted, L.

doi:10.1111/j.1365-2125.1975.tb01589.x

Cited by 14 publications

(2 citation statements)

References 6 publications

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“…A number of drug interactions with CPA have been reported in humans. It seems that the underlying mechanism is inhibition of CYP enzymes for the drug interactions with allopurinol [163], chloramphenicol [228], sulphaphenazole [228], chlorpromazine [163,229], fluconazole [230], ranitidine [231], and thiotepa (triethylenethiophosphoramide) [232]. Drug interactions have also been reported with dexamethasone [163], prednisolone [233], phenobarbitone [234], and phenytoin [169] due to induction of CPA metabolism.…”

Section: Pharmacokinetic Drug Interactionsmentioning

confidence: 99%

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

Zhang¹,

Tian²,

Zhou³

2006

CDTH

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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.

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Section: Pharmacokinetic Drug Interactionsmentioning

confidence: 99%

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

Zhang¹,

Tian²,

Zhou³

2006

CDTH

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“…1996 Blackwell Science Ltd British Joitrnal of Clinical Pharmacology 41,[13][14][15][16][17][18][19] …”

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confidence: 99%

Cyclophosphamide pharmacokinetics in children

Yule

Boddy²,

Cole

et al. 1996

Brit J Clinical Pharma

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1 Cyclophosphamide pharmacokinetics were measured in 38 children with cancer. 2 A high degree of inter-patient variation was seen in all pharmacokinetic parameters. Cyclophosphamide half-life varied between 1.1 and 16.8 h, clearance varied between 1.2 and 10.61 h-l m P 2 and volume of distribution varied between 0.26 and 1.48 1 kg-'. 3 The half-life of cyclophosphamide was prolonged at high dose levels (P = 0.008). 4 Children who had received prior treatment with dexamethasone showed a mean increase in clearance of 2.5 1 h-l m P 2 (P=O.OOl) presumably as a result of CYP450 enzyme induction. 5 Treatment with allopurinol or chlorpromazine was associated with a significant increase in cyclophosphamide half-life (P < 0.001 in both cases). 6 Dose and concurrent treatment may influence cyclophosphamide metabolism in vivo and thus potentially alter the drugs therapeutic effect.

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An Overview of Cyclophosphamide and Ifosfamide Pharmacology

Fleming

1997

Pharmacotherapy

102

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Cyclophosphamide and ifosfamide are alkylating agents administered to treat malignant disease. They are prodrugs and require activation by hepatic microsomal enzymes before being metabolized to their respective cytotoxic species, phosphoramide mustard and ifosfamide mustard. These species alkylate DNA, forming DNA‐DNA cross‐links that result in inhibition of DNA synthesis and cell death. Resistance to oxazaphosphorines is poorly understood, although increased aldehyde dehydrogenase activity may be a significant factor. Although both compounds share a common metabolic pathway, 4‐hydroxylation of ifosfamide occurs at a slower rate and to a lesser extent than that of cyclophosphamide. This difference significantly alters the toxicity profile of ifosfamide. Leukopenia is the dose‐limiting toxicity of cyclophosphamide, and neurotoxicity is the dose‐limiting toxicity of ifosfamide when preventive measures are taken to reduce urotoxicity. With recent findings concerning their basic and clinical pharmacology, the therapeutic index of these compounds can be improved.

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The effect of chloramphenicol and sulphaphenazole on the biotransformation of cyclophosphamide in man.

Cited by 14 publications

References 6 publications

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

Cyclophosphamide pharmacokinetics in children

An Overview of Cyclophosphamide and Ifosfamide Pharmacology

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