Across subjects, folate absorption, bile folate flux, and body folate stores were larger than prior estimates. Marrow folate uptake and pteroylpolyglutamate synthesis, recycling, and catabolism are saturable processes. Visceral pteroylpolyglutamate was an immediate precursor of plasma p-aminobenzoylglutamate. The model is a working hypothesis with derived features that are explicitly model-dependent. It successfully quantitated folate metabolism, encouraging further rigorous testing.

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ABSTRACT.A new compact accelerator mass spectrometry (AMS) system dedicated to the measurement of radiocarbon has been commissioned at the Accium BioSciences headquarters in Seattle. The entire facility (including ancillary laboratories for the preparation of graphite targets) has been designed to handle samples with a wide range of 14 C concentrations. In this paper, we discuss the technical details of the new facility and present performance test results demonstrating state-of-theart capabilities. In particular, modern samples can be readily measured with 0.3% precision and accuracy, machine background levels are consistently in the low 10 -16 ( 14 C/ 12 C), and chemical background is approximately equivalent to a fraction of modern of 0.004. In addition, when 100-times-modern samples were processed, no increase in background was observed, either during sample processing or during AMS measurement. This corresponds to a dynamic range for 14 C analysis of 6 orders of magnitude.

Determination of the pharmacokinetics and absolute bioavailability of an experimental compound, SCH 900518, following a 89.7 nCi (100 μg) intravenous (iv) dose of 14C-SCH 900518 2 h post 200 mg oral administration of nonradiolabeled SCH 900518 to six healthy male subjects has been described. The plasma concentration of SCH 900518 was measured using a validated LC–MS/MS system, and accelerator mass spectrometry (AMS) was used for quantitative plasma 14C-SCH 900518 concentration determination. Calibration standards and quality controls were included for every batch of sample analysis by AMS to ensure acceptable quality of the assay. Plasma 14C-SCH 900518 concentrations were derived from the regression function established from the calibration standards, rather than directly from isotopic ratios from AMS measurement. The precision and accuracy of quality controls and calibration standards met the requirements of bioanalytical guidance (U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Veterinary Medicine. Guidance for Industry: Bioanalytical Method Validation (ucm070107), May 2001. ). The AMS measurement had a linear response range from 0.0159 to 9.07 dpm/mL for plasma 14C-SCH 900158 concentrations. The CV and accuracy were 3.4–8.5% and 94–108% (82–119% for the lower limit of quantitation (LLOQ)), respectively, with a correlation coefficient of 0.9998. The absolute bioavailability was calculated from the dose-normalized area under the curve of iv and oral doses after the plasma concentrations were plotted vs the sampling time post oral dose. The mean absolute bioavailability of SCH 900518 was 40.8% (range 16.8–60.6%). The typical accuracy and standard deviation in AMS quantitative analysis of drugs from human plasma samples have been reported for the first time, and the impact of these parameters on quantitative analysis was further assessed using the Z factor. The use of the lowest achievable LLOQ Z =0 derived from statistical analysis of the control and low-concentration standards for AMS measurements is proposed in future studies.

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