A Mass Balance Study to Evaluate the Biotransformation and Excretion of [<sup>14</sup>C]‐Triamcinolone Acetonide following Oral Administration

Argenti, Domenick; Jensen, Bo Boye Busk; Hensel, Russell; Bordeaux, Kirk G.; Schleimer, Robert P.; Bickel, Carol A.; Heald, Donald

doi:10.1177/00912700022009413

Cited by 33 publications

(22 citation statements)

References 20 publications

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“…Together, these data strongly suggest that the ketone is found on the hydroxyacetone group of flunsiolide. Furthermore, P450s are known to catalyze the formation of acetic acid from alcohol (BellParikh and Guengerich, 1999), and triamcinolone acetonide has previously been shown to form the same P450-mediated 21-carboxy metabolite (Argenti et al, 2000). Two metabolites with m/z 431 (RT = 15.8 and 17.6 minutes) were also observed, consistent with the formation of a ketone, and the additional loss of HF.…”

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confidence: 79%

Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes

et al. 2012

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Asthma is one of the most prevalent diseases in the world, for which the mainstay treatment has been inhaled glucocorticoids (GCs). Despite the widespread use of these drugs, approximately 30% of asthma sufferers exhibit some degree of steroid insensitivity or are refractory to inhaled GCs. One hypothesis to explain this phenomenon is interpatient variability in the clearance of these compounds. The objective of this research is to determine how metabolism of GCs by the CYP3A family of enzymes could affect their effectiveness in asthmatic patients. In this work, the metabolism of four frequently prescribed inhaled GCs, triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate, by the CYP3A family of enzymes was studied to identify differences in their rates of clearance and to identify their metabolites. Both interenzyme and interdrug variability in rates of metabolism and metabolic fate were observed. CYP3A4 was the most efficient metabolic catalyst for all the compounds, and CYP3A7 had the slowest rates. CYP3A5, which is particularly relevant to GC metabolism in the lungs, was also shown to efficiently metabolize triamcinolone acetonide, budesonide, and fluticasone propionate. In contrast, flunisolide was only metabolized via CYP3A4, with no significant turnover by CYP3A5 or CYP3A7. Common metabolites included 6b-hydroxylation and Δ 6-dehydrogenation for triamcinolone acetonide, budesonide, and flunisolide. The structure of Δ 6 -flunisolide was unambiguously established by NMR analysis. Metabolism also occurred on the D-ring substituents, including the 21-carboxy metabolites for triamcinolone acetonide and flunisolide. The novel metabolite 21-nortriamcinolone acetonide was also identified by liquid chromatography-mass spectrometry and NMR analysis.

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confidence: 79%

Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes

et al. 2012

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“…Radiolabeled organic xenobiotics are widely used in biomedical science for bioavailability and biotransformation studies in both animals and humans (Dain et al, 1994;Reith et al, 1998;Argenti et al, 2000). The isotope of choice for these studies is 14 C, a low energy ␤-emitter usually detected by decay counting.…”

Section: C-labeled (R)-6-[amino(4-chlorophenyl)(1-methyl-1h-imidazol-mentioning

confidence: 99%

Evaluation of Accelerator Mass Spectrometry in a Human Mass Balance and Pharmacokinetic Study–Experience with¹⁴C-labeled (R)-6-[Amino(4- chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1- methyl-2(1H)-quinolinone (R115777), a Farnesyl Transferase Inhibitor

Garner¹,

Goris²,

Laenen³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Accelerator mass spectrometry (AMS) has been used in a human mass balance and metabolism study to analyze samples taken from four healthy male adult subjects administered nanoCurie doses of the farnesyl transferase inhibitor 14 analysis showed that drug-related 14 C was present in the plasma samples with C max values ranging from 1.6055 to 2.9074 dpm/ml (1.0525-1.9047 g/ml) at t max ‫؍‬ 2 to 3 h. The C max values for acetonitrile extracts of plasma samples ranged from 0.3724 to 0.7490 dpm/ml in the four male subjects. Drug-related 14 C was eliminated from the body both in the urine and the feces, with a mean total recovery of 79.8 ؎ 12.9% in the feces and 13.7 ؎ 6.2% in the urine. The majority of drug-related radioactivity in urine and feces was excreted within the first 48 h. High-performance liquid chromatography (HPLC)-AMS profiles were generated from radioactive parent drug plus metabolites from pooled diluted urine, plasma, and methanolic feces extracts and matched to retention times of synthetic reference substances, postulated as metabolites. All HPLC separations used no more than 5 dpm injected on-column. The radioactive metabolite profiles obtained compared well with those obtained using liquid chromatography/tandem mass spectometry. This study demonstrates the use of AMS in a human phase I study in which the administered radioactive dose was at least 1000-fold lower than that used for conventional radioactive studies. C-labeled (R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone ([ 14 C]R115777Radiolabeled organic xenobiotics are widely used in biomedical science for bioavailability and biotransformation studies in both animals and humans (Dain et al., 1994;Reith et al., 1998;Argenti et al., 2000). The isotope of choice for these studies is 14 C, a low energy ␤-emitter usually detected by decay counting.14 C is a useful labeling agent for drugs because it is often possible to incorporate 14 C in a chemically and metabolically stable position of the xenobiotic molecule. However, decay counting as a method of analyzing 14 C is an inefficient process owing to the long radioactive half-life of this isotope of 5740 years. In any one year, only 0.012% of 14 C atoms decay in a sample; to detect 1 dpm requires approximately 10 9 atoms to be present in a sample.14 C-labeled drugs are widely used in human mass balance studies, in which an inventory of the parent drug and metabolites can be measured in urine, feces, and plasma Young et al., 2001). In such studies, an appropriate dose of the 14 C-labeled drug is administered to healthy subjects, and the concentrations of radioactivity in plasma, urine, and feces are determined by decay counting.In the mid-70s, accelerator mass spectrometry (AMS 1 ), a nuclear physics technique, was developed primarily for use in radiocarbon dating (Bennett et al., 1977;Nelson et al., 1977). AMS uses a Van de Graaff accelerator operating at millions of volts to provide the energy potential to permit the outer valen...

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“…As shown in Table 2 and Figure 6 this method could be used as an additional useful tool to the semi-quantitative SUV method or to any other method (Kesner et al 2006, Zhong et al 2008 to estimate radioactivity value in tumor or any mouse organs. The possible application for this technique could be useful for the organ radioactivity dosimetry studies (Smith T 1992, Virta et al 2008 that required before mass balance study (Argenti et al 2000, Beumer et al 2005 may be performed in humans.…”

Section: Resultsmentioning

confidence: 99%

Practical method for radioactivity distribution analysis in small-animal PET cancer studies

Slavine

Antich

2008

Applied Radiation and Isotopes

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We present a practical method for radioactivity distribution analysis in small-animal tumors and organs using positron emission tomography imaging with a calibrated source of known activity and size in the field of view. We reconstruct the imaged mouse together with a source under the same conditions, using an iterative method, Maximum Likelihood Expectation-Maximization with System Modeling, capable of delivering high resolution images. Corrections for the ratios of geometrical efficiencies, radioisotope decay in time and photon attenuation are included in the algorithm. We demonstrate reconstruction results for the amount of radioactivity within the scanned mouse in a sample study of osteolytic and osteoblastic bone metastasis from prostate cancer xenografts. Data acquisition was performed on the small-animal PET system which was tested with different radioactive sources, phantoms and animals to achieve high sensitivity and spatial resolution. Our method uses high resolution images to determine the volume of organ or tumor and the amount of their radioactivity, has the possibility of saving time, effort and the necessity to sacrifice animals. This method has utility for prognosis and quantitative analysis in small-animal cancer studies, and will enhance the assessment of characteristics of tumor growth, identifying metastases, and potentially determining the effectiveness of cancer treatment. The possible application for this technique could be useful for the organ radioactivity dosimetry studies.

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A Mass Balance Study to Evaluate the Biotransformation and Excretion of [¹⁴C]‐Triamcinolone Acetonide following Oral Administration

Cited by 33 publications

References 20 publications

Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes

Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes

Evaluation of Accelerator Mass Spectrometry in a Human Mass Balance and Pharmacokinetic Study–Experience with¹⁴C-labeled (R)-6-[Amino(4- chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1- methyl-2(1H)-quinolinone (R115777), a Farnesyl Transferase Inhibitor

Practical method for radioactivity distribution analysis in small-animal PET cancer studies

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A Mass Balance Study to Evaluate the Biotransformation and Excretion of [14C]‐Triamcinolone Acetonide following Oral Administration

Cited by 33 publications

References 20 publications

Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes

Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes

Evaluation of Accelerator Mass Spectrometry in a Human Mass Balance and Pharmacokinetic Study–Experience with14C-labeled (R)-6-[Amino(4- chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1- methyl-2(1H)-quinolinone (R115777), a Farnesyl Transferase Inhibitor

Practical method for radioactivity distribution analysis in small-animal PET cancer studies

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Resources

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A Mass Balance Study to Evaluate the Biotransformation and Excretion of [¹⁴C]‐Triamcinolone Acetonide following Oral Administration

Evaluation of Accelerator Mass Spectrometry in a Human Mass Balance and Pharmacokinetic Study–Experience with¹⁴C-labeled (R)-6-[Amino(4- chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1- methyl-2(1H)-quinolinone (R115777), a Farnesyl Transferase Inhibitor