Determination of rapamycin: quantification of the sodiated species by an ion trap mass spectrometer as an alternative to the ammoniated complex analysis by triple quadrupole

Pieri, Maria; Miraglia, Nadia; Castiglia, Loredana; Genovese, Giuliana; Basilicata, Pascale; Simonelli, Angela; Acampora, Antonio

doi:10.1002/rcm.2168

Cited by 9 publications

(11 citation statements)

References 34 publications

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“…Analysis was carried out in a manner similar to that of Pieri et al (17) using an Agilent Technologies series 1100 Capillary LC/MSD-Trap equipped with a binary pump, online degasser, column oven, thermostated micro autosampler, and ion-trap mass spectrometer (17). Separations were conducted by reverse-phase chromatography using a 150 mm Â 0.5 mm inner diameter micro-column packed with 5 m Luna C8(2) stationary phase obtained from Phenomemex (Torrance, CA) operated at 60jC.…”

Section: Methodsmentioning

confidence: 99%

Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors

Granville

Warfel²,

Tsurutani³

et al. 2007

Clinical Cancer Research

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Purpose: Human and murine preneoplastic lung lesions induced by tobacco exposure are characterized by increased activation of theAkt/mammalian target of rapamycin (mTOR) pathway, suggesting a role for this pathway in lung cancer development. To test this, we did studies with rapamycin, an inhibitor of mTOR, in A/J mice that had been exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Experimental Design: Tumorigenesis was induced by i.p. injection of NNK, and rapamycin was administered1or 26 weeks after NNK administration. Biomarkers associated with mTOR inhibition were assessed in lung and/or surrogate tissues using immunohistochemistry and immunoblotting. Rapamycin levels were measured using mass spectroscopy. Results: Rapamycin was administered on a daily (5 of 7 days) regimen beginning 26 weeks after NNK decreased tumor size, proliferative rate, and mTOR activity. Multiplicity was not affected. Comparing this regimen with an every-other-day (qod) regimen revealed that rapamycin levels were better maintained with qod administration, reaching a nadir of 16.4 ng/mL, a level relevant in humans. When begun 1 week after NNK, this regimen was well tolerated and decreased tumor multiplicity by 90%. Tumors that did develop showed decreased phenotypic progression and a 74% decrease in size that correlated with decreased proliferation and inhibition of mTOR. Conclusions:Tobacco carcinogen^induced lung tumors in A/J mice are dependent upon mTOR activity because rapamycin markedly reduced the development and growth of tumors. Combined with the Food and Drug Administration approval of rapamycin and broad clinical experience, these studies provide a rationale to assess rapamycin in trials with smokers at high risk to develop lung cancer.

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Section: Methodsmentioning

confidence: 99%

Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors

Granville

Warfel²,

Tsurutani³

et al. 2007

Clinical Cancer Research

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“…The concentration of sirolimus in the circulation varies with time after placement. Many means can be used to determine the sirolimus concentration in whole blood (Volosov et al, 2001;Napoli and Taylor, 2001;Streit et al, 2002;Vogeser et al, 2002;Pieri et al, 2005;Morris et al, 2006). However, sirolimus concentrations in the tissue vary significantly with the distance from the stents and with time.…”

Section: Methodsmentioning

confidence: 97%

Determination of sirolimus in rabbit arteries using liquid chromatography separation and tandem mass spectrometric detection

Jun

Rodila

Watson

et al. 2007

Biomedical Chromatography

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Sirolimus, an effective immunosuppressive agent, is used for drug eluting stents. During stent development, an analytical method for the determination of sirolimus in tissue needs to be established. Normally, tissue samples are homogenized and then analyzed against the calibration standards prepared in a tissue homogenate. This approach provides insufficient control of the homogenization process. In this paper, tissue quality control samples were introduced for the optimization of the homogenization process during method development, but also allowance for the performance evaluation of the entire analytical process. In addition, a new approach using rabbit blood as a homogenization medium was developed to stabilize sirolimus in rabbit tissue homogenates. Calibration standards and quality controls were prepared by spiking different sirolimus working solutions into rabbit blood. Homogenization quality control samples were prepared by injecting other sirolimus working solutions into empty test tubes and pre-cut arteries within pre-defined masses. A high-throughput homogenization procedure was optimized based on the specific chemical properties of sirolimus. The linear dynamic range was between 49.9 pg/mL and 31.9 ng/mL to accommodate the expected artery homogenate concentrations. Additionally, quality controls in rabbit blood were also used in the extraction to support the calibration standards. The accuracy and precision of the quality controls in rabbit blood reflect the extraction performance and the accuracy and precision of the homogenization tissue quality controls reflect the overall performance of the method. The mean bias was between -4.5 and 0.2% for all levels of quality controls in the blood and between 4.8 and 14.9% for all levels of the homogenization tissue quality controls. The CVs of all concentration levels were < or =5.3% for the quality controls in blood and < or =9.2% for the homogenization tissue quality controls. The method was successfully applied to determine the concentration of sirolimus in the rabbit arteries.

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“…5 (15). The LC/ESI-MSMS method was characterised by a LOD of 0.7 ng/mL and a LLOQ of 2.4 ng/mL for sirolimus (16) and by a LOD of 0.6 ng/mL and a LLOQ of2.9 ng/mL for everolimus.…”

Section: Lciesi-msms Methodsmentioning

confidence: 99%

Stability of Sirolimus and Everolimus Measured by Immunoassay Techniques in Whole Blood Samples from Kidney Transplant Patients

Capone¹,

Gentile²,

Polichetti³

et al. 2008

Int J Immunopathol Pharmacol

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The measurement of blood concentration of immunosuppressive drugs is strongly recommended because of the narrow therapeutic range. An important aspect in the therapeutic monitoring of a drug is its possible degradation. This paper is aimed at investigating the stability of two widely-used immunosuppressants, sirolimus and everolimus. Short (storage at 30 degrees C for 3 or 7 days) and long term (storage at -20 degrees C for 0-90 days with a single freeze-thaw cycle) stability of sirolimus and everolimus in whole blood samples from kidney transplant patients were examined by using MEIA and FPIA. Sirolimus and everolimus samples stored at 30 degrees C in light for up to a week showed a decrement in concentration of 5.2 percent and 6.1 percent, respectively. Our findings on long term stability for both sirolimus and everolimus highlight the possibility of storing samples at -20 degrees C for up to 90 days, without the need to use lower storage temperatures. The results have important implications for patients living far from laboratories where drug concentration is measured or when the storing of blood samples is needed for pharmacokinetic studies.

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Determination of rapamycin: quantification of the sodiated species by an ion trap mass spectrometer as an alternative to the ammoniated complex analysis by triple quadrupole

Cited by 9 publications

References 34 publications

Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors

Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors

Determination of sirolimus in rabbit arteries using liquid chromatography separation and tandem mass spectrometric detection

Stability of Sirolimus and Everolimus Measured by Immunoassay Techniques in Whole Blood Samples from Kidney Transplant Patients

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