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Volume10, Issue 12 (Suppl)
J Proteomics Bioinform, an open access journal
ISSN: 0974-276X
Page 91
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World Biomarkers & Pharma Biotech 2017
December 07-09, 2017
December 07-09, 2017 | Madrid, Spain
&
20
th
International Conference on
PHARMACEUTICAL BIOTECHNOLOGY
9
th
WORLD BIOMARKERS CONGRESS
JOINT EVENT ON
Accelerator mass spectrometry-enabled microtracer study to evaluate the human mass balance of
KD101: Method challenges for analysis of a volatile oil
Howard Lee
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
T
he large majority of drugs and not volatile and amenable to standard analytical techniques. Volatile compounds pose
a different set of challenges, requiring changes to the total sample preparation procedure and often analytical method.
We encountered such situation during a human microtracer study (180 nCi human oral dose) of compound KD101, a single
isomeric oil, (-)α-Cedrene (206.23 g/mol). A total of 6 subjects were administered 400 mg of unlabeled KD101 admixed
with 180 nCi of radiolabeled drug as a tracer. Detection of the radiolabel was performed using graphite based Accelerator
Mass Spectrometry (AMS), with support from Liquid Scintillation Counting (LSC) for early urinary time-points. Post-
administration, cumulative urine and fecal voids were collected for 288 hr post-dose. Serial blood collections were taken
frequently post-administration and then daily for the duration of the study. Preliminary work showed the KD101 could be
completely removed under vacuum concentration in the absence of any trapping agent or biological matrix. This problem was
exacerbated by the AMS processing method where samples are also evacuated under vacuum for torch-sealing inside quartz
combustion (oxidation to gaseous carbon dioxide, prior to reduction to graphite). We found an acceptable technique to limit
volatility losses through the pretreatment of all samples with an excess of tributyrin prior to concentration. The tributyrin
served thus as both a carbon source and a chemical trapping agent. Sucrose was also tested but showed little ability to “capture”
the compound during dry-down. We showed that parent compound recovery could be improved from <10 to 89% recovery
using 2.0 mg of tributyrin per sample or LC fraction, and a minimum dry-down time (20 min). The overall results of the
study validated the dilution method. Mean mass balance recovery was 85.21% (77.96% in urine, 7.26% feces). This is
considered a good mass balance recovery given the fact that it was difficult to control for losses due to compound volatility.
The concentration decay in the plasma was largely bi-exponential after the absorption period, with a wandering baseline out
to 288 hr post-dose, with occasional “jumps” in concentration, which was attributed to the displacement of compound in fat
depots. Metabolite radiochromatograms from urine and plasma showed intact parent in plasma with metabolites exclusively
explaining the urinary components. In summary, we achieved satisfactory results for the mass balance and metabolism of a
volatile oil using a chemical trapping agent. The detriment was a lowering of overall detection sensitivity (e.g. 0.88 dpm/mL
of plasma vs. 0.05 dpm/mL of unmodified plasma), but sensitivity was still sufficient to achieve mass balance and perform
metabolite profiling using highly sensitive AMS detection.
Recent Publications
1. Kim YK, Kim A, Park SJ, Lee H. New tablet formulation of tacrolimus with smaller interindividual variability may
become a better treatment option than the conventional capsule formulation in organ transplant patients. Drug
Design Dev Ther. 2017 (11): 2861-2869
2. Kim Y, Kim A, Lee S, Choi SH, Lee DY, Song JS, Lee H, Jang IJ, Yu KS. Pharmacokinetics, Safety and Tolerability of
Tedizolid Phosphate After Single-Dose Administration in Healthy Korean Male Subjects. Clin Ther. 2017. Sep;39(9):
1849-1857
Biography
Howard Lee is the Founder and Director of the Center for Convergence Approaches in Drug Development (CCADD). Dr. Lee serves as a Professor at the
Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University. Dr. Lee is also appointed at Seoul
National University College of Medicine and Hospital, affiliated with the Department of Clinical Pharmacology and Therapeutics. Dr. Lee previously served
as Head of Global Strategy and Planning, Clinical Trials Center, SNUH. As of August 2017, Dr. Lee was appointed Chair of the Graduate Program in Clinical
Pharmacology, Seoul National University. Dr. Lee has spearhead the introduction of Accelerator Mass Spectrometry (AMS)-enabled exploratory early clinical drug
development studies to the Korean biopharmaceutical R&D sector, which has awarded Dr. Lee 2 government grants.
howardlee@snu.ac.krHoward Lee, J Proteomics Bioinform 2017, 10:12(Suppl)
DOI: 10.4172/0974-276X-C1-110