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Drug Metabolism Letters


ISSN (Print): 1872-3128
ISSN (Online): 1874-0758

Research Article

Unequal Absorption of Radiolabeled and Nonradiolabeled Drug from the Oral Dose Leads to Incorrect Estimates of Drug Absorption and Circulating Metabolites in a Mass Balance Study

Author(s): Ryan H. Takahashi*, Jae H. Chang, Jodie Pang, Xiaorong Liang and Shuguang Ma

Volume 13, Issue 1, 2019

Page: [37 - 44] Pages: 8

DOI: 10.2174/1872312813666181129162237


Background: Mass balance studies conducted using radiolabeled material (14C or 3H) definitively characterize the Absorption, Metabolism, and Excretion (AME) of a drug. A critical aspect of these studies is that the radiotracer maintains its proportion to total drug from its administration to its complete elimination from the body. In the study of GDC-0276 in beagle dogs, we observed that the 14C radiotracer proportion (specific activity) varied through the study.

Method: High resolution-accurate mass spectrometric measurements of 12C and 14C isotopes of GDC- 0276 and its metabolites in plasma and excreta samples were used to determine the apparent specific activities, which were higher than the specific activity of the dosing formulation. Drug concentrations were adjusted to the observed specific activities to correct the readouts for GDC-0276 AME and PK.

Results: The enrichment of 14C, which resulted in higher specific activities, was consistent with faster and more extensive absorption of the radiotracer from the dosing formulation. This resulted in overestimating the dose absorbed, the extent of elimination in urine and bile, and the exposures to circulating metabolites. These biases were corrected by the specific activities determined for study samples by mass spectrometry.

Conclusion: Assuming that the radiotracer was proportional to total drug throughout a radiolabeled study was not valid in a 14C study in beagle dogs. This presumably resulted from unequal absorption of the radiotracer and nonradiolabeled test articles from the oral dose due to inequivalent solid forms. We were able to provide a more accurate description of the AME of GDC-0276 in dogs by characterizing the differential absorption of the radiotracer.

Keywords: Mass balance, preclinical studies, drug development, radiotracers, ADME, pharmacokinetics.

Graphical Abstract
Beumer, J.H.; Beijnen, J.H.; Schellens, J.H. Mass balance studies, with a focus on anticancer drugs. Clin. Pharmacokinet., 2006, 45, 33-58.
Penner, N.; Klunk, L.J.; Prakash, C. Human radiolabeled mass balance studies: objectives, utilities and limitations. Biopharm. Drug Dispos., 2009, 30, 185-203.
Schadt, S.; Bister, B.; Chowdhury, S.K.; Funk, C.; Hop, C.E.C.A.; Humphreys, W.G.; Igarashi, F.; James, A.D.; Kagan, M. Khojasteh. S.C.; A Decade in the MIST: Learnings from investigations of drug metabolites in drug development under the “Metabolites in Safety Testing” regulatory guidances. Drug Metab. Dispos., 2018, 46(6), 865-878.
FDA (2016) Guidance for industry: safety testing of drug metabolites.(US Department of Health and Human Services FaDA, Center for Drug Evaluation and Research, Silver Spring, MD
Roffey, S.J.; Obach, R.S.; Gedge, J.I.; Smith, D.A. What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab. Rev., 2007, 39, 17-43.
Obach, R.S.; Nedderman, A.N.; Smith, D.A. Radiolabelled mass-balance excretion and metabolism studies in laboratory animals: are they still necessary? Xenobiotica, 2012, 42, 46-56.
White, R.E.; Evans, D.C.; Hop, C.E.; Moore, D.J.; Prakash, C.; Surapaneni, S.; Tse, F.L. Radiolabeled mass-balance excretion and metabolism studies in laboratory animals: A commentary on why they are still necessary. Xenobiotica, 2013, 43, 219-225.
Ghibellini, G.; Leslie, E.M.; Brouwer, K.L. Methods to evaluate biliary excretion of drugs in humans: an updated review. Mol. Pharm., 2006, 3, 198-211.
Guiney, W.J.; Beaumont, C.; Thomas, S.R.; Robertson, D.C.; McHugh, S.M.; Koch, A.; Richards, D. Use of Entero-Test, a simple approach for non-invasive clinical evaluation of the biliary disposition of drugs. Br. J. Clin. Pharmacol., 2011, 72, 133-142.
Hop, C.E.; Wang, Z.; Chen, Q.; Kwei, G. Plasma-pooling methods to increase throughput for in vivo pharmacokinetic screening. J. Pharm. Sci., 1998, 87, 901-903.
Bachir-Cherif, D.; Blum, D.; Braendli-Baiocco, A.; Chaput, E.; Pacheco, G.C.; Flint, N.; Haiker, M.; Hoflack, J.C.; Justies, N.; Neff, R. Characterization of post-surgical alterations in the bile duct-cannulated rat. Xenobiotica, 2011, 41, 701-711.
Lee, J.H.; Park, Y.J.; Oh, J.H.; Lee, Y.J. Decrease in gastrointestinal absorption of roxithromycin in bile duct cannulated rats due to depletion of bile salts. Biopharm. Drug Dispos., 2013, 34, 360-364.
Dalvie, D.K.; Khosla, N.B.; Navetta, K.A.; Brighty, K.E. Metabolism and excretion of trovafloxacin, a new quinolone antibiotic, in Sprague-Dawley rats and beagle dogs. Effect of bile duct cannulation on excretion pathways. Drug Metab. Dispos., 1996, 24, 1231-1240.
Poondru, S.; Chaves, J.; Yuen, G.; Parker, B.; Conklin, E.; Singh, M.; Nagata, M.; Gill, S. Mass balance, pharmacokinetics, and metabolism of linsitinib in cancer patients. Cancer Chemother. Pharmacol., 2016, 77, 829-837.
Castellino, S.; O’Mara, M.; Koch, K.; Borts, D.J.; Bowers, G.D.; MacLauchlin, C. Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity. Drug Metab. Dispos., 2012, 40, 139-150.
Johnson, T.R.; Tan, W.; Goulet, L.; Smith, E.B.; Yamazaki, S.; Walker, G.S.; O’Gorman, M.T.; Bedarida, G.; Zou, H.Y.; Christensen, J.G. Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects. Xenobiotica, 2015, 45, 45-59.
Yu, C.; Chen, C.L.; Gorycki, F.L.; Neiss, T.G. A rapid method for quantitatively estimating metabolites in human plasma in the absence of synthetic standards using a combination of liquid chromatography/mass spectrometry and radiometric detection. Rapid Commun. Mass Spectrom., 2007, 21, 497-502.
Yi, P.; Luffer-Atlas, D. A radiocalibration method with pseudo internal standard to estimate circulating metabolite concentrations. Bioanalysis, 2010, 2, 1195-1210.

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