Takahashi Ryan H, Chang Jae H, Pang Jodie, Liang Xiaorong, Ma Shuguang
Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, United States.
Drug Metab Lett. 2019;13(1):37-44. doi: 10.2174/1872312813666181129162237.
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.
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.
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.
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.
使用放射性标记物质（14C或3H）进行的质量平衡研究能够明确表征药物的吸收、代谢和排泄（AME）情况。这些研究的一个关键方面是放射性示踪剂从给药到完全从体内消除的过程中，要保持其与总药物的比例关系。在比格犬的GDC - 0276研究中，我们观察到14C放射性示踪剂比例（比活度）在整个研究过程中发生了变化。
采用高分辨率精确质谱法测量血浆和排泄物样本中GDC - 0276及其代谢物的12C和14C同位素，以确定表观比活度，该比活度高于给药制剂的比活度。将药物浓度调整为观察到的比活度，以校正GDC - 0276 AME和PK的读数。
14C的富集导致比活度升高，这与放射性示踪剂从给药制剂中更快、更广泛的吸收一致。这导致高估了吸收的剂量、尿液和胆汁中的消除程度以及循环代谢物的暴露量。通过质谱法为研究样本确定的比活度对这些偏差进行了校正。
在比格犬的14C研究中，假设在整个放射性标记研究中放射性示踪剂与总药物成比例是无效的。这可能是由于不等同的固体形式导致放射性示踪剂和非放射性标记测试品从口服剂量中吸收不均等。通过表征放射性示踪剂的差异吸收，我们能够更准确地描述GDC - 0276在犬体内的AME情况。
