Pharmacokinėtics of intravenous and oral cyclophosphamide in the presence of methotrexate and fluorouracil

Bruijn, E. A. de; Slee, P. H. Th. J.; Oosterom, A.T. van; Lameijer, D. W.; Roozendaal, K. J.; Tjaden, U. R.

doi:10.1007/bf01956871

Cited by 15 publications

(16 citation statements)

References 14 publications

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“…CYC is a prodrug that is converted in the liver to its active alkylating metabolite, phosphoramide mustard, which binds to DNA and reacts with purine bases to form double-stranded adducts [67,69]. It can be administered either orally or intravenously [70–72]. Plasma PK of CYC was described by a two-compartment model.…”

Section: Cyclophosphamidementioning

confidence: 99%

Pharmacokinetic modeling of therapies for systemic lupus erythematosus

Yang

Sherwin

Tian

et al. 2015

Expert Review of Clinical Pharmacology

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With the increasing use of different types of therapies in treating autoimmune diseases such as systemic lupus erythematosus (SLE), there is a need to utilize pharmacokinetic (PK) strategies to optimize the clinical outcome of these treatments. Various PK analysis approaches, including population PK modeling and physiologically based PK modeling, have been used to evaluate drug PK characteristics and population variability or to predict drug PK profiles in a mechanistic manner. This review outlines the PK modeling of major SLE therapies including immunosuppressants (methotrexate, azathioprine, mycophenolate and cyclophosphamide, among others) and immunomodulators (intravenous immunoglobulin). It summarizes the population PK modeling, physiologically based PK modeling and model-based individualized dosing strategies to improve the therapeutic outcomes in SLE patients.

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Section: Cyclophosphamidementioning

confidence: 99%

Pharmacokinetic modeling of therapies for systemic lupus erythematosus

Yang

Sherwin

Tian

et al. 2015

Expert Review of Clinical Pharmacology

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“…Oral administration of CPA is usually given at low doses (75− 200 mg/day) when used as an immunosuppressive agent and as a component in the CMF regimen of breast cancer [141,142]. CPA is well absorbed after oral administration.…”

Section: Pharmacokinetics Of Oxazaphosphorinesmentioning

confidence: 99%

“…The peak concentration appears 1 hour following oral drug administration. The oral bioavailability of CPA is 85−100% [141][142][143][144][145], and a fraction of drug is metabolized due to the first-pass effect in the liver and gut. At high doses (0.7 g/m 2 ), CPA has an 87.7% oral bioavailability [146].…”

Section: Pharmacokinetics Of Oxazaphosphorinesmentioning

confidence: 99%

Reversal of Resistance to Oxazaphosphorines

Zhang¹,

Tian²,

Zhu³

et al. 2006

CCDT

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The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO) and trofosfamide are one important group of alkylating agents. However, resistance is the major hindrance for success of oxazaphosphorine chemotherapy. The mechanism of resistance to oxazaphosphorines is not fully identified, but recently some novel insights into these aspects have been generated by using sensitive analytical techniques and powerful pharmacogenetic techniques. Potential mechanisms for oxazaphosphorine resistance include decreased activation by cytochrome P450s (e.g. CYP3A4, CYP2C9 and CYP2B6), increased deactivation of the agents by deactivating enzymes such as aldehyde dehydrogenases (ALDHs), increased cellular thiol level, increased DNA repair capacity, and altered cellular apoptotic response to DNA repair, e.g. deficient apoptosis due to lack of cellular mechanisms to result in cell death following DNA damage. In addition, decreased cellular accumulation of cytotoxic species of oxazaphosphorines may also play a role in the resistance. This review highlights the pharmacology of oxazaphosphorine anticancer drugs and possible agents that reverse the resistance to these agents. Possible agents that can overcome oxazaphosphorine resistance include inducers of CYPs, modulators of GSTs and ALDHs, modulators of DNA repair process, antisense oligonucleotides against genes encoding various enzymes and signalling proteins, and novel gene delivery systems. Most of these agents have been investigated in preclinical studies and promising results have been observed. To date, several types of these agents are being evaluated in Phase III trials in cancer patients. Further studies are needed to identify the molecular targets associated with resistance to oxazaphosphorines.

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“…More recently, we reported on the bioavailability of CY as administered in the CMF regimen; thus. CY resorption and elimination were studied in the presence of MTX and 5-FU [5]. In the present study, we report on the systemic exposure of oral CY in 22 patients treated according to the CMF regimen.…”

Section: Introductionmentioning

confidence: 99%

Bioavailability of Cyclophosphamide in the CMF Regimen

Gheuens

Slee²

1990

Oncol Res Treat

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Cyclophosphamid (Cy) wurde bei 22 Patientinnen mit Mammakarzinom routinemäßig innerhalb des CMF-Regimes verabfolgt. Sie erhielten Cy 75 mg/m²/Tag × 14 Tage p.o., Methotrexat (MTX) 30 mg/m² und 5-Fluorouracil (5-FU) 500 mg/m² i.v. am Tag 1 und 8. Die Verabreichungssequenz war stets gleich, nämlich 1. Cy, 2. MTX und 3. 5-FU. Zur Bestimmung von Cyim Blut wurde die kapilläre Gaschromatographie angewandt. Die Bioverfügbarkeit (F) konnte bei 14 Patientinnen bestimmt werden, da Cy in derselben Dosis auch i.v. verabfolgt wurde. Die Daten der systemischen Exposition des oralen Cy bei den anderen 8 Patientinnen wurden mit denjenigen der ersten 14 Patientinnen verglichen, bei denen F bestimmt wurde. Die mittlere F betrug 0,85 ± 0,22 (85% ± 22%), bei einer Patientin 0,43 (43%). Weiterhin hatten 3 Patientinnen, die nur mit Cy p.o. behandelt wurden, die niedrigsten F-Werte, nämlich 0,45, 0,49 und 0,50. Der Vergleich der Patientencharakteristika mit den pharmakokinetischen Daten wies darauf hin, daß dem Alter eine prädiktive Bedeutung für die Eliminations-Halbwertszeit ti/z des i.v. Cy zukommen könnte. Die jüngsten Patientinnen zeigten die kürzesten t i/z und waren auch diejenigen mit der niedrigsten F. Dieser Befund verlangt eine Ausweitung der Studie wie auch eine Überprüfung des Cy-Stoffwechsels als Funktion des Alters. Das dürfte für prämenopausale Patientinnen von besonderer Bedeutung sein, da bekannt ist, daß diese Gruppe von der chemotherapeutischen Behandlung mit dem CMF-Regime besonders profitiert.

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Pharmacokinėtics of intravenous and oral cyclophosphamide in the presence of methotrexate and fluorouracil

Cited by 15 publications

References 14 publications

Pharmacokinetic modeling of therapies for systemic lupus erythematosus

Pharmacokinetic modeling of therapies for systemic lupus erythematosus

Reversal of Resistance to Oxazaphosphorines

Bioavailability of Cyclophosphamide in the CMF Regimen

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