Distribution radiolabelled drugs

The first attempt to radiolabel drug particles (instead of polymers like polystyrene or Teflon particles) for pharmaceutical aerosols was carried out on fenoterol and salbutamol by Kohler et al. [12] Scheme 3). However, it was later found that their method would change the particle size distribution of the labelled aerosol, resulting in a coarser aerosol than the imlabelled product. After subsequent improvement by Summers et al. [18] Scheme 4), this method has become widely used for radiolabelling MDIs. It is preferred over other methods as it does not involve extraction with tetraphenylarsonium chloride and chloroform. 

Using radiolabeled drug candidate, perform tissue distribution, with whole body autoradiography, in rodents after single-dose and multiple-dose (if appropriate) administration. 

One of the most significant medical applications of radiolabelled compounds is for PET scans. These are important diagnostic and research tools that can be used to study the distribution of drugs or biomolecules in the body, and for imaging of organs. 

Fig. 5.4 Distribution of radiolabeled drugs in humans monitored by PET. (a) A brain image of ["CJtemozolomide, showing high localization of radioactivity in the tumor (glioma), (b) A thoracic image of [ C]DACA scan, showing localization in the myocardium and tumor (mesothelioma).

Residues are evaluated to determine the extent of uptake of the veterinary drug, its distribution throughout the body, and its elimination. Normally, contemporary residue depletion studies establish tissue concentrations in a radiolabeled drug study, in which total residues and parent compound are determined at several pre-determined times between zero time and a time beyond the proposed withdrawal time. As well as total residues, which include free and bound components, the study quantifies major metabolites. These are compounds contributing 10% or more of total radioactivity or that are present at a concentration of > 0.10 mg/kg. Metabolism studies enable identification of the marker residue and target tissue. The marker residue must give assurance that, when its concentration is at or below the MRL, total residues satisfy ADI requirements. 

In order to determine the metabolic fate of a radiolabeled drug, radioactivity in plasma, urine bile and feces is profiled for metabolite distribution. Metabolite profiling in muraglitazar study is described below. 

Techniques for quantitative ADME typically employ radiolabeled drugs to look at tissue distribution either in homogenized samples or by whole body autoradiography. Whole body autoradiography involving the location and quantification of radiolabeled material in thin frozen sections of tissue can be particularly useful. Plasma protein binding and metabolism studies also benefit from the use of radio-labeled material. 

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. 

Radiolabeling of a candidate drug to observe its distribution within brain ... 

Regardless of the type of aerosol products to be radiolabelled, a fimdamental requirement in radiolabelling aerosol products is that the radiolabel must associate with the drug in such a way that not only the radiolabel distribution matches the drug distribution but also that the radiolabel distribution matches that of the unlabelled commercial product. 

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