The Biotransformation of Cyclophosphamide in Man: Influence of Prednisone

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

doi:10.1111/j.1600-0773.1974.tb00739.x

Cited by 34 publications

(8 citation statements)

References 5 publications

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“…An in vitro study has identified glucocorticoid receptor binding sites in the promoter region of the CYP2C19 gene and demonstrated upregulation of CYP2C19 in response to dexamethasone, supporting an inductive effect of glucocorticoids on CYP2C19 (5). An in vivo study has also demonstrated an inductive effect of a 12-to 15-day course of prednisone on the metabolism of cyclophosphamide, a substrate of both CYP2C19 and CYP2C9 (10). In addition, CYP3A4, which glucocorticoids have been shown to induce at higher doses (7), contributes to the metabolism of voriconazole (27).…”

Section: Discussionmentioning

confidence: 98%

Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

Dolton

Ray

Chen

et al. 2012

Antimicrob Agents Chemother

248

272

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Section: Discussionmentioning

confidence: 98%

Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

Dolton

Ray

Chen

et al. 2012

Antimicrob Agents Chemother

248

272

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“…Glucocorticoids also have been reported to affect the biotransformation of cyclophosphamide via their effects on hepatic microsomal enzymes . In two rodent studies, concurrent prednisolone appeared to inhibit the hepatic metabolism of cyclophosphamide to its active forms .…”

Section: Discussionmentioning

confidence: 99%

“…24 Interestingly, reports in people have also been conflicting; although Bagley et al showed no change in cyclophosphamide metabolism in people following a single large IV dose of prednisolone, Faber et al noted an increased rate of serum elimination of cyclophosphamide following 12 days of prednisone pretreatment, which was hypothesized to be due to hepatic enzyme induction by prednisone. 23,25 To our knowledge, the effects of glucocorticoids on the biotransformation of cyclophosphamide have not been studied in the dog; however, any effects that glucocorticoids might have on the systemic exposure to active metabolites would be expected to alter the toxicities and efficacy of cyclophosphamide.…”

Section: Discussionmentioning

confidence: 99%

Risk factors for development of sterile haemorrhagic cystitis in canine lymphoma patients receiving oral cyclophosphamide: a case–control study

Gaeta

Brown

Cohen

et al. 2012

Vet Comparative Oncology

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Sterile haemorrhagic cystitis (SHC) is a known risk of cyclophosphamide treatment; however, most canine reports are case series. This case-control study examined risk factors for SHC in dogs with lymphoma receiving oral cyclophosphamide. Twenty-two dogs with SHC and 66 control dogs were identified. On univariate analysis, SHC risk factors included age (P = 0.041), induction protocol (P = 0.021) and cumulative cyclophosphamide dose (P = 0.002). On multivariate analysis, increasing cumulative cyclophosphamide dose was associated with increased risk of SHC and the 'short' induction protocol (protocol 1) was associated with decreased risk. Controlling for age and induction protocol, odds of SHC increased by 2.21 per 750 mg m(-2) increase in cyclophosphamide dose (P = 0.001). SHC from oral cyclophosphamide is a predominately delayed toxicity resulting from high cumulative doses.

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“…In addition, a number of drugs which are prescribed to lupus nephritis patients during cyclophosphamide therapy may influence bioactivation. For example, prednisone, although an inhibitor of CYP2C19 in vitro [31], is also an inducer of cyclophosphamide metabolism [32], and as such, may enhance the bioactivation ratio. Such gene–environment interactions, combined with the ability of cyclophosphamide to auto‐induce its own metabolism [33], may preclude using a simple genotyping approach to identify patients at risk of therapeutic failure with this drug.…”

Section: Discussionmentioning

confidence: 99%

The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation

Helsby

Hui

Goldthorpe

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The prodrug cyclophosphamide requires bioactivation by liver CYP enzymes.• Controversy exists about which CYP isoforms are important in the in vitro bioactivation of this drug.• Recent clinical studies have highlighted a role for either CYP2C19 or CYP2B6 in the therapeutic response to cyclophosphamide in lupus patients. • However, the role of these isoforms in the bioactivation of cyclophosphamide in lupus patients has not been previously demonstrated. WHAT THIS STUDY ADDS• Low bioactivation of cyclophosphamide by human liver appears to be dependent on a combination of both CYP2C19 and CYP2B6 loss of function variants.• In a preliminary study of lupus patients poor bioactivation of cyclophosphamide was also observed in those individuals who had at least one loss of function allele at either CYP2C19 or CYP2B6. AIMSThe role of CYP pharmacogenetics in the bioactivation of cyclophosphamide is still controversial. Recent clinical studies have suggested a role for either CYP2C19 or CYP2B6. The aim of this study was to clarify the role of these pharmacogenes. METHODSWe used a combined in vitro-in vivo approach to determine the role of these pharmacogenes in the bioactivation of the prodrug to 4-hydroxy cyclophosphamide (4-OHCP). Cyclophosphamide metabolism was determined in a human liver biobank (n = 14) and in patients receiving the drug for treatment of lupus nephritis (n = 16) RESULTSIn livers of known CYP2C19 and CYP2B6 genotype and protein expression we observed that there was a combined role for both CYP2C19 and CYP2B6 in the bioactivation of cyclophosphamide in vitro. The presence of at least one loss of function (LoF) allele at either CYP2C19 or CYP2B6 resulted in a significant decrease in both Vmax (P = 0.028) and CLint (P = 0.0017) compared with livers with no LoF alleles. This dual genotype relationship was also observed in a preliminary clinical study, with patients who had Ն1 LoF allele at either CYP2C19 or CYP2B6 also displaying significantly (P = 0.0316) lower bioactivation of cyclophosphamide. The mean 4-OHCP : CP bioactivation ratio was 0.0014 (95% CI 0.0007, 0.002) compared with 0.0071 (95% CI 0.0001, 0.014) in patients with no LoF alleles at either of these genes. CONCLUSIONSThe presence of Ն1 LoF allele(s) at either CYP2B6 or CYP2C19 appeared to result in decreased bioactivation of cyclophosphamide both in vitro and in patients. Further clinical studies to confirm this relationship are warranted.

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The Biotransformation of Cyclophosphamide in Man: Influence of Prednisone

Cited by 34 publications

References 5 publications

Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

Risk factors for development of sterile haemorrhagic cystitis in canine lymphoma patients receiving oral cyclophosphamide: a case–control study

The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation

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