Use of An Intravenous Microdose of 14C-labeled drug and Accelerator Mass Spectrometry to measure Absolute Oral Bioavailability in Dogs; Cross-comparison of Assay Methods by Accelerator Mass Spectrometry and Liquid Chromatography-Tandem Mass Spectrometry

doi:10.2133/dmpk.24.130

Drug Metabolism and Pharmacokinetics

Volume 24, Issue 2, 2009, Pages 130-138

https://doi.org/10.2133/dmpk.24.130 Get rights and content

Summary:

A technique utilizing simultaneous intravenous microdosing of ¹⁴C-labeled drug with oral dosing of non-labeled drug for measurement of absolute bioavailability was evaluated using R-142086 in male dogs. Plasma concentrations of R-142086 were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and those of ¹⁴C-R-142086 were measured by accelerator mass spectrometry (AMS). The absence of metabolites in the plasma and urine was confirmed by a single radioactive peak of the parent compound in the chromatogram after intravenous microdosing of ¹⁴C-R-142086 (1.5 μg/kg). Although plasma concentrations of R-142086 determined by LC-MS/MS were approximately 20% higher than those of ¹⁴C-R-142086 as determined by AMS, there was excellent correlation (r = 0.994) between both concentrations after intravenous dosing of ¹⁴C-R-142086 (0.3 mg/kg). The oral bioavailability of R-142086 at 1 mg/kg obtained by simultaneous intravenous microdosing of ¹⁴C-R-142086 was 16.1%, this being slightly higher than the value (12.5%) obtained by separate intravenous dosing of R-142086 (0.3 mg/kg). In conclusion, on utilizing simultaneous intravenous microdosing of ¹⁴C-labeled drug in conjunction with AMS analysis, absolute bioavailability could be approximately measured in dogs, but without total accuracy. Bioavailability in humans may possibly be approximately measured at an earlier stage and at a lower cost.

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Cited by (16)

Status of the AMS system at Yamagata University
2019, Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms
Citation Excerpt :
Thus, dead carbon carrier is necessary to graphitize a sample with a mass of 1 mgC. This study indicates that sodium benzoate, which was first used by Miyaji et al. [23], is an appropriate carrier for microdosing studies with 14C-AMS. The YU-AMS system and an automated graphitization line were installed at YU in 2009.
An accelerator mass spectrometry (AMS) system and an automated graphitization line were installed at Yamagata University (YU) in 2009. Approximately 2000 samples are measured per year using the YU-AMS system. The long-term stability of the system was assessed by measuring the standard sample IAEA-C7 graphitized by the automated graphitization line. In March 2014, a second automated graphitization line and an additional ion source for the YU-AMS system were installed to meet the requirement of ¹⁴C measurement for pharmacological and medical applications. A phosphoric acid treatment system was also developed for the radiocarbon dating of calcium carbonate (CaCO₃) in shell and coral samples. Performance tests on the new YU-AMS system were carried out by measuring the C-series standard samples (C1-C9) and oxalic acid II (HOxII) obtained from IAEA and NIST, respectively. The results of the ¹⁴C concentration pMC are in good agreement with the consensus values. Performance tests for medical applications were also carried out by measuring the ¹⁴C concentration of ¹⁴C-glucose in human plasma.
Accelerator mass spectrometry analysis of <sup>14</sup>C-oxaliplatin concentrations in biological samples and <sup>14</sup>C contents in biological samples and antineoplastic agents
2015, Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms
Citation Excerpt :
The carbon content of the sample was calculated from the amount of CO2 gas measured with the EA for graphite preparation. Oxaliplatin 14C-content was obtained by subtracting the both contributions of 14C-contents for the carrier (sodium benzoate) and for each biological sample of serum, urine, and supernatant of fecal homogenate, respectively [9]. 14C-contents of the biological samples and the antineoplastic agents were obtained by subtracting the contribution of sodium benzoate.
Accelerator mass spectrometry (AMS) is expected to play an important role in microdose trials. In this study, we measured the ¹⁴C concentration in ¹⁴C-oxaliplatin-spiked serum, urine and supernatant of fecal homogenate samples in our Yamagata University (YU) – AMS system. The calibration curves of ¹⁴C concentration in serum, urine and supernatant of fecal homogenate were linear (the correlation coefficients were ⩾0.9893), and the precision and accuracy was within the acceptance criteria.
To examine a ¹⁴C content of water in three vacuum blood collection tubes and a syringe were measured. ¹⁴C was not detected from water in these devices. The mean ¹⁴C content in urine samples of 6 healthy Japanese volunteers was 0.144 dpm/mL, and the intra-day fluctuation of ¹⁴C content in urine from a volunteer was little. The antineoplastic agents are administered to the patients in combination. Then, ¹⁴C contents of the antineoplastic agents were quantitated. ¹⁴C contents were different among 10 antineoplastic agents; ¹⁴C contents of paclitaxel injection and docetaxel hydrate injection were higher than those of the other injections.
These results indicate that our quantitation method using YU-AMS system is suited for microdosing studies and that measurement of baseline and co-administered drugs might be necessary for the studies in low concentrations.
Proteomic profiling and identification of significant markers from high-grade osteosarcoma after cryotherapy and irradiation
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Phase-0/microdosing studies using PET, AMS, and LC-MS/MS: a range of study methodologies and conduct considerations. Accelerating development of novel pharmaceuticals through safe testing in humans–a practical guide
2017, Expert Opinion on Drug Delivery
Approaches to intravenous clinical pharmacokinetics: Recent developments with isotopic microtracers
2016, Journal of Clinical Pharmacology
Analytical approaches to support microdose studies in drug discovery and development
2015, Advanced LC-MS Applications in Bioanalysis

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Regular ArticleUse of An Intravenous Microdose of 14C-labeled drug and Accelerator Mass Spectrometry to measure Absolute Oral Bioavailability in Dogs; Cross-comparison of Assay Methods by Accelerator Mass Spectrometry and Liquid Chromatography-Tandem Mass Spectrometry

Summary:

J. Pharm. Biomed. Anal.

Accelerator mass spectrometry (AMS): recent experience of its use in a clinical study and the potential future of the technique

Xenobiotic.

Evaluation of accelerator mass spectrometry in a human mass balance and pharmacokinetic study-experience with 14C-labeled(R)-6-[amino(4-chlorophenyl)(1-methyl-1 H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (R115777), a farnesyl transferase inhibitor

Drug Metab. Dispos.

The application of accelerator mass spectrometry to absolute bioavailability studies in humans: simultaneous administration of an intravenous microdose of 14C-nelfinavir mesylate solution and oral nelfinavir to healthy volunteers

J. Clin. Pharmacol.

Determination of the bioavailability of [14C]-hexaminolevulinate using accelerator mass spectrometry after intravesical administration to human volunteers

J. Clin. Pharmacol.

Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs

Clin. Pharmacol Ther.

Regular Article
Use of An Intravenous Microdose of ¹⁴C-labeled drug and Accelerator Mass Spectrometry to measure Absolute Oral Bioavailability in Dogs; Cross-comparison of Assay Methods by Accelerator Mass Spectrometry and Liquid Chromatography-Tandem Mass Spectrometry

The application of accelerator mass spectrometry to absolute bioavailability studies in humans: simultaneous administration of an intravenous microdose of ¹⁴C-nelfinavir mesylate solution and oral nelfinavir to healthy volunteers