Radiolabeling/radiolabeled drug disposition

Cook, C.E., Perez, R.M., Jeffcoat, A.R., and Brine, D.R., Phencyclidine disposition in humans after small doses of radiolabeled drug, Fed. Proc., 42, 2566, 1983. 

Disposition, rates and routes of elimination of radiolabelled drug... 

Ward et al. [125] investigated the disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation, after the administration of 0.5, 1.5, and 5 mg doses of the drug. The pharmacokinetics of primaquine in the experimental model was dependent on dose size. Increasing the dose from 0.5 to 5 mg produced a significant reduction in clearance from 11.6 to 2.9 mL/min. This decrease was accompanied by a disproportionate increase in the value of the area under the curve from 25.4 to 1128.6 pg/mL, elimination half-life from 33.2 to 413 min, and volume of distribution from 547.7 to 1489 mL. Primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected perfusate after the 0.5 mg dose, it was the principal perfusate metabolite after 5 mg dose. Primaquine was subject to extensive biliary excretion at all doses, the total amount of 14C-radioactivity excreted in the bile decreased from 60 to 30%i as the dose of primaquine was increased from 0.5 to 5 mg. 

A human ADME study conducted using radiolabeled form of the NCE (usually referred to as 14C-human ADME) is a study that in most cases is required prior to start of the Phase III clinical trials and the data from the human ADME study are important components of the nonclinical sections of the NDA submission and drug label. The objectives of 14C-human ADME studies are to determine the total disposition of the NCE, encompassing mass balance, routes of NCE/metabolite elimination, and biotransformation pathways. 

Davis CB, Garver EM, Kwok DC, Urbanski JJ. Disposition of metabolically radiolabeled CE9.1—a macaque-human chimeric anti-human CD4 monoclonal antibody— in transgenic mice bearing human CD4. Drug Metab Dispos 1996 24 1032-1037. 

The following section will focus on the detailed ADME studies conducted during the drug development process to help understand the disposition of a drug in nonclinical species and in humans. Since these studies are typically conducted with radiolabeled compound, a short section on the use of radiolabeled compound is included here along with a section on tissue distribution studies conducted to support the human ADME study. 

Krishna R, Yao M, Srinivas NR, Shah V, Pursley JM, Arnold M, Vacharajani NN. Disposition of radiolabeled BMS-204352 in rats and dogs. Biopharm Drug Dispos 2002 23 41 6. 

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