Cyclopentenyl cytosine: Interspecies predictions based on rodent plasma and urine kinetics

Zaharko, Daniel S.; Kelley, James A.; Tomaszewski, Joseph E.; Hegedũs, Lajos; Hartman, Neil R.

doi:10.1007/bf00194539

Cited by 9 publications

(2 citation statements)

References 12 publications

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“…CPEC was mainly cleared into urine unchanged for all different species studied [51]. The plasma concentration was best described by a three compartment model consisting of a central compartment (extracellular fluid) and two cellular compartments.…”

Section: Pharmacokinetics Animalmentioning

confidence: 99%

Cyclopentenyl Cytosine (CPEC): An Overview of its in vitro and in vivo Activity

Schimmel¹,

Gelderblom²,

Guchelaar

2007

CCDT

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The experimental cytotoxic drug cyclopentenyl cytosine (CPEC) is an analogue of cytidine. Besides its antiviral effect, its potential use in the treatment of cancer has become an important area of research. CPEC is activated by intracellular phosphorylation ultimately forming its metabolite CPEC-TP. CPEC-TP is a non competitive inhibitor of cytidine-5'-triphosphate synthetase (CTP-synthetase), an important enzyme in the formation of CTP. Studies have shown that cancer cells have a high CTP synthetase activity, thus making them interesting targets for chemotherapy. CPEC has been preclinically studied in different malignancy models. In vitro results on leukemia show activity in the nanomolar range on several cell lines. However in vivo results are conflicting and the findings vary from increase in life span over 100% to only limited effectiveness. Interesting results have been obtained in colorectal and neuroblastoma cells. In several neuroblastoma cell lines incubation with CPEC in combination with cytarabine or gemcitabine has resulted in increased cell death compared to incubation with with only one of the agents. CPEC has been studied in a phase I trial in patients with solid tumors. In five of 26 patients unexplained cardiotoxicity (extreme hypotension) occurred. The cardiotoxic effects could not be reproduced in animal models. However, precautions should be taken when using this drug in future clinical trials. Low dosage of CPEC seems necessary and intensive cardiac monitoring is advisable. In this manuscript, it is demonstrated that CPEC has an anti-cancer effect in several tumor models: CPEC might be a potentially useful drug in anticancer treatment.

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Section: Pharmacokinetics Animalmentioning

confidence: 99%

Cyclopentenyl Cytosine (CPEC): An Overview of its in vitro and in vivo Activity

Schimmel¹,

Gelderblom²,

Guchelaar

2007

CCDT

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“…Pharmacokinetic data from animals revealed major interspecies differences. In rodents and dogs renal excretion of the unchanged drug was the primary route of elimination, whereas in primates deamination to CPEU was dominant (Blaney et al, 1990;Zaharko et al, 1991). Although deamination to CPEU accounted for a significant part of the elimination in humans, elimination of CPEC occurred mainly by renal excretion of the unchanged drug (Politi et al, 1995).…”

Section: Introductionmentioning

confidence: 97%

Quantitative analysis of the experimental cytotoxic drug cyclopentenyl cytosine and its metabolite in plasma with HPLC tandem mass spectrometry

Schimmel¹,

Lenthe²,

Leen³

et al. 2008

Biomedical Chromatography

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The cytotoxic drug cyclopentenyl cytosine (CPEC) is currently being investigated in early clinical trials. Monitoring of plasma levels is required for pharmacokinetic analysis and management of toxicity. This paper describes the analysis of CPEC and cyclopentenyl uracil (CPEU) in plasma by HPLC-electrospray ionization tandem mass spectrometry. The calibration curves for CPEC and the metabolite CPEU were linear up to 10 microm with correlation coefficients of 0.997 (SD = 0.002, n = 10) and 0.997 (SD = 0.004, n = 10), respectively. The detection limit for CPEC was 0.03 and 0.12 microM for CPEU. The intra- and interassay coefficients of variation for CPEC and CPEU were less then 10%. The usefulness of the method was demonstrated by analyzing CPEC and CPEU in plasma of a patient treated with CPEC. HPLC with electrospray ionization tandem mass spectrometry allowed rapid and sensitive determination of CPEC and CPEU levels in plasma.

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Phase I clinical trial of continuous infusion cyclopentenyl cytosine

Politi

Xie

Dahut

et al. 1995

Cancer Chemother. Pharmacol.

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Cyclopentenyl cytosine (CPE-C) is an investigational drug that is active against human solid tumor xenografts. The 5'-triphosphate of CPE-C inhibits CTP synthase, and depletes CTP and dCTP pools. We conducted a phase I clinical trial of CPE-C given as a 24-h continuous i.v. infusion every 3 weeks in 26 adults with solid tumors. The starting dose rate, 1 mg/m2 per h, was selected on the basis of both preclinical studies and pharmacokinetic data from two patients obtained after a test dose of 24 mg/m2 CPE-C as an i.v. bolus. Dose escalation was guided by clinical toxicity. A total of 87 cycles were given, and ten patients received four or more cycles. The mean CPE-C steady-state plasma levels (Cpss) increased linearly from 0.4 microM to 3.1 microM at dose levels ranging from 1 to 5.9 mg/m2 per h (actual body weight); the mean total body clearance was 146 +/- 38 ml/min per m2. CPE-C was eliminated by both renal excretion of intact drug and deamination to cyclopentenyl uracil in an apparent 2:1 ratio. CTP synthase activity in intact bone marrow mononuclear cells was inhibited by 58% to 100% at 22 h compared to matched pretreatment samples at all CPE-C dose levels. When all data were combined, flux through CTP synthase was decreased by 89.6% +/- 3.1% at 22 h (mean +/- SE, n = 16), and remained inhibited by 67.6% +/- 7.7% (n = 10) for at least 24 h post-CPE-C infusion. Granulocyte and platelet toxicities were dose-dependent, and dose-limiting myelosuppression occurred during the initial cycle in two of three patients treated with 5.9 mg/m2 per h. Four of 11 patients (4 of 20 cycles) who received 4.7 mg/m2 per h CPE-C experienced hypotension 24-48 h after completion of the CPE-C infusion during their first (n = 2), third (n = 1) and sixth cycles (n = 1), respectively. Two of these patients died with refractory hypotension despite aggressive hydration and cardiopulmonary resuscitation. One of 12 patients (28 total cycles) treated with 3.5 mg/m2 per h CPE-C experienced orthostatic hypotension during cycle 1, and this patient had a second episode of orthostatic hypotension at a lower dose (3.0 mg/m2 per h). Hypotension was not seen in patients receiving < or = 2.5 mg/m2 per h CPE-C.(ABSTRACT TRUNCATED AT 400 WORDS)

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Cyclopentenyl cytosine: Interspecies predictions based on rodent plasma and urine kinetics

Cited by 9 publications

References 12 publications

Cyclopentenyl Cytosine (CPEC): An Overview of its in vitro and in vivo Activity

Cyclopentenyl Cytosine (CPEC): An Overview of its in vitro and in vivo Activity

Quantitative analysis of the experimental cytotoxic drug cyclopentenyl cytosine and its metabolite in plasma with HPLC tandem mass spectrometry

Phase I clinical trial of continuous infusion cyclopentenyl cytosine

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