Disposition, pharmacokinetics, and metabolism of 14C-fotemustine in cancer patients

Ings, R. M. J.; Gray, Alan; Taylor, A. R.; Gordon, Ben; Breen, Matthew; Hiley, M. P.; Brownsill, R. D.; Marchant, NJ; Richards, R.; Wallace, Duncan G.; Hughes, Thomas E.; Thomas, R. J.; Williams, James W.; Lucas, Catherine; Campbell, David B.

doi:10.1016/0277-5379(90)90166-q

Cited by 15 publications

(8 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, both in the presence and in the absence of GSH, 90-95% of fotemustine (I) decomposed first into DEP-isocyanate (III) and a 2-chloroethanediazohydroxide intermediate (II), before GSH conjugation of DEP-isocyanate (III) to form DEP-SG (IV) or hydrolysis of DEP-isocyanate (III) to form V and VI occurs. The conversion of fotemustine (I) into the heterocyclic compound VIII, both in the presence and in the absence of GSH, can be explained by oxidative dechlorination and subsequent cyclization (40). Our results with SK&F 525A, however, indicate that oxidative enzymes in rat liver Sg fractions are apparently of minor importance in the dechlorination of fotemustine (I).…”

Section: Discussionmentioning

confidence: 51%

“…Our results with SK&F 525A, however, indicate that oxidative enzymes in rat liver Sg fractions are apparently of minor importance in the dechlorination of fotemustine (I). In microsomes of rat liver, however, a small but significant contribution of cytochrome P450 enzymes to the dechlorination of fotemustine (I) into VIII was suggested (40). We suggest that dechlorination of fotemustine (I) may also result from intramolecular nucleophilic displacement of chlorine by the amide nitrogen of fotemustine (I).…”

Section: Discussionmentioning

confidence: 75%

“…We did not observe this reaction in rat liver Sg fractions with HEPES buffered to pH = 7.4 (Figure 1; Table 1); however, this is in contrast to unbuffered aqueous media (pH = 4.4). Denitrosylation of fotemustine (I) into VII was previously observed in minor amounts in rat liver microsomes (40). In rats treated intraperitoneally with fotemustine (I), traces (<1%) of this product (VII) were recently also found to be excreted in urine.…”

Section: Discussionmentioning

confidence: 91%

See 2 more Smart Citations

Chemical and Glutathione Conjugation-Related Degradation of Fotemustine: Formation and Characterization of a Glutathione Conjugate of Diethyl (1-Isocyanatoethyl)phosphonate, a Reactive Metabolite of Fotemustine

Commandeur

Kanter²,

Baar³

et al. 1994

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Fotemustine is a chemotherapeutic drug for the treatment of melanoma. In this study, we investigated the metabolic and chemical stability of fotemustine with 31P-NMR and FAB-MS. In the absence of GSH, 95% of fotemustine decomposed rapidly into a reactive diethyl ethylphosphonate (DEP) isocyanate, both in rat liver S9 fraction and in HEPES buffer (pH = 7.4). DEP-isocyanate in turn hydrolyzed rapidly into diethyl (1-aminoethyl)phosphonate, which reacted subsequently with the parent DEP-isocyanate. The remaining 5% of fotemustine was shown to decompose via dechlorination into diethyl [1-(3-nitroso-2-oxoimidazolidin-1-yl)ethyl]-phosphonate. In the presence of GSH, hydrolysis of DEP-isocyanate was blocked, and a glutathione conjugate (DEP-SG) was formed instead. DEP-SG was relatively stable at 37 degrees C in HEPES buffer. Only two minor and as yet unidentified decomposition products were formed. Addition of N-acetyl-L-cysteine (NAC) to DEP-SG in HEPES buffer converted DEP-SG rapidly into the corresponding NAC conjugate of DEP-isocyanate (DEP-NAC). The formation of DEP-SG from DEP-isocyanate and GSH appeared to be spontaneous. The extent of formation of DEP-SG from fotemustine and GSH was equal in both enzymatically active and inactive rat liver S9 fractions. In the presence and in the absence of GSH, the half-lives of decomposition (t1/2) of fotemustine were 33 +/- 6 and 27 +/- 3 min, respectively. The formation of the DEP-isocyanate and 2-chloroethanediazohydroxide intermediates from fotemustine appeared to be rate limiting, and not the hydrolysis of the DEP-isocyanate nor its conjugation to GSH. Active or inactive rat liver S9 fractions accelerated the decomposition of fotemustine slightly; i.e., the t1/2 of fotemustine decreased from 39 +/- 3 to 29 +/- 1 min. Further knowledge of the metabolic and chemical stability of fotemustine and DEP-isocyanate will contribute to a better understanding of fotemustine-related cytostatic effects and toxic side effects and to the design of chemoprotection against undesired toxic side effects.

show abstract

Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

Chemical and Glutathione Conjugation-Related Degradation of Fotemustine: Formation and Characterization of a Glutathione Conjugate of Diethyl (1-Isocyanatoethyl)phosphonate, a Reactive Metabolite of Fotemustine

Commandeur

Kanter²,

Baar³

et al. 1994

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…They also found that FM lost half its activity in 30 min and virtually all activity within 120 min. In ViVo pharmacokinetic studies on this drug have been conducted by a number of authors (Gordon et al, 1989;Ings et al, 1990;Bartosek et al 1991;Tranchand et al, 1993). Estimates of the half-life of the intact drug in plasma have ranged from 12 min in cynomolus monkeys (drug administered as a bolus) to 23 min in a human (drug administered as an intravenous infusion over a 1 h period (Gordon et al, 1989).…”

Section: Bioassay Of Fm Stability In Culture and Selectivity Formentioning

confidence: 99%

Mechanism of Action of Fotemustine, a New Chloroethylnitrosourea Anticancer Agent: Evidence for the Formation of Two DNA-Reactive Intermediates Contributing to Cytotoxicity

et al. 1997

View full text Add to dashboard Cite

Methyl excision repair deficient human tumor cells (Mer-) were found to be hypersusceptible to killing by the antimelanoma agent fotemustine (FM) implicating alkylation of O6 guanine as the major contributor to toxicity. Preincubation of the drug in aqueous solution for 5 min resulted in an immediate reduction in cytotoxicity (35-50%), in vitro DNA alkylation (31%), and DNA interstrand cross-linking (40%) followed by a second reaction with considerably slower kinetics. Electrospray ionisation mass spectrometry (ESI-MS) showed that in aqueous solution FM rearranged rapidly to form either a metastable tautomer or decomposed to form a highly reactive diazohydroxide (t1/2 < 2 min). These results suggest the presence of two DNA-reactive species relevant to biological activity. Coincubation of ellagic acid (an inhibitor of O6-guanine alkylation) with FM inhibited in vitro ISC, suggesting that the O6-chloroethyl lesion is the predominant cause of the cross-link. On the basis of these findings, we propose that FM breaks down to form a short-lived intermediate, 2-chloroethyldiazohydroxide, which rapidly generates O6-guanine lesions responsible for the drug's initial activity and a long lived iminol tautomer responsible for the remaining O6 guanine alkylation and cytotoxicity.

show abstract

“…Fotemustine is usually administered following a schedule consisting of 3 doses every week, followed by maintenance doses administered every 3 weeks. On the grounds of pharmacokinetic data suggesting incomplete drug elimination after weekly intervals, [ 20 , 21 ] we decided to assess whether the use of a biweekly regimen allowed administration of higher dose than the standard 100 mg/m 2 dose approved per label indication in a population of patients with recurrent GBM.…”

Section: Introductionmentioning

confidence: 99%

High-dose fotemustine in temozolomide-pretreated glioblastoma multiforme patients

Marinelli

Cerbone²,

Cordua³

et al. 2018

Medicine

View full text Add to dashboard Cite

Background:Glioblastoma multiforme (GBM) is a rare and deadly disease, with a reported average incidence rate of 3.19 cases per 100,000 inhabitants. Fotemustine, a third-generation nitrosourea with an alanine phosphor carrier that facilitates cellular penetration, has been extensively investigated in the setting of recurrent/progressive disease after initial treatment. Fotemustine is usually administered following a schedule consisting of 3 doses every week, followed by maintenance doses administered every 3 weeks.Methods:In this phase I/II trial, we aimed to assess whether the use of a biweekly regimen allowed administration of higher dose than the standard 100 mg/m2 dose approved per label indication in a population of patients with recurrent GBM. In this phase I/II trial, fotemustine was administered intravenously over 1 hour every 2 weeks at either 120 or 140 mg/m2 doses for up to 1 year, until disease progression, unacceptable toxicity, or patient's request to withdraw from the study. The phase I part of the trial was conducted following the classic 3+3 study design. The phase II part of the trial was a single-arm study. The primary efficacy endpoint was the percentage of patients who had not progressed after 24 weeks (PFS-24).Results:Thirty-seven patients were enrolled in this phase I/II trial from August 2006 to November 2011. Treatment was well tolerated in the overall population. Main severe toxicity was grades 3 and 4 thrombocytopenia, which occurred in 4 of 6 patients treated at the 140 mg/m2 dose level and in 3 of 31 patients treated at 120 mg/m2. Median PFS and overall survival were 12.1 (1–40.2) weeks and 19.7 (1–102) weeks, respectively.Conclusion:We conclude that fotemustine can be safely administered at 120 mg/m2 biweekly. The efficacy of such modified schedule and doses should be compared to the biweekly schedule at 80 mg2 and the standard weekly schedule at 80 to 100 mg/m2.

show abstract

Disposition, pharmacokinetics, and metabolism of 14C-fotemustine in cancer patients

Cited by 15 publications

References 5 publications

Chemical and Glutathione Conjugation-Related Degradation of Fotemustine: Formation and Characterization of a Glutathione Conjugate of Diethyl (1-Isocyanatoethyl)phosphonate, a Reactive Metabolite of Fotemustine

Chemical and Glutathione Conjugation-Related Degradation of Fotemustine: Formation and Characterization of a Glutathione Conjugate of Diethyl (1-Isocyanatoethyl)phosphonate, a Reactive Metabolite of Fotemustine

Mechanism of Action of Fotemustine, a New Chloroethylnitrosourea Anticancer Agent: Evidence for the Formation of Two DNA-Reactive Intermediates Contributing to Cytotoxicity

High-dose fotemustine in temozolomide-pretreated glioblastoma multiforme patients

Contact Info

Product

Resources

About