Absorption
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II.L.1 II.L.2 II.L.3 II.L.4 II.L.5 II.L.6
Radiokinetics and Mass Balance in Dogs . . . . . . . . . . . . . . . . . . . . . . . . . Mass Balance Study in Rats . . . . Blood/Plasma Radiokinetics in Rats . . . . . . . . . . . . . . . . . . . . . . . . . Bile Fistula Study in Rats . . . . . . . Diaplacental Transfer Study in Rats . . . . . . . . . . . . . . . . . . . . . . . . . Milk Transfer Study in Rats . . . .
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INTRODUCTION
The use of radiolabeled molecules allows a drug and its labeled metabolites to be followed throughout the body and excreta over time. The radioactivity concentration can be tracked in blood and plasma as well as in tissues. Whether the drug with its specific radioactivity administered to the body is completely captured can be proven by calculating the so-called ‘mass balance’. Whereas the radioactivity measurement alone does not allow distinguishing between drug and metabolite(s), samples obtained from the described studies should be also used for standard determination of the drug and its known metabolites, receiving information about the drug and the known metabolite kinetics directly. The gap between radioactivity concentrations and the concentrations determined by direct bioanalytical methods defines the contribution of unknown metabolites. Using one and the same set of studies with equally withdrawn samples for determination of all radiokinetic and pharmacokinetic data possible is not only economically favorable, but allows illuminating comparisons with a minimum of assumptions and therefore high confidence to interpretation. Radiokinetic studies deliver the key data of absorption and elimination to which all data and statements of other investigations have to fit – or in case of conflict need a plausible explanation at least. As examples in the following chapter, the frequently used radiokinetic studies in dogs and rats are described, including placental transfer and milk
transfer in rats. Investigations in other species can often be performed similarly. The final choice of species should be done in consensus with toxicology (at a later stage of development including cancerogenicity and segment II studies), regarding the metabolic patterns of in vitro cross-species comparisons and regarding the pharmacological in vivo model. A suggestion of necessary types of radiokinetic studies and general hints for conducting those animal ADME studies can be found in Campbell DB, Jochemsen R (1994). Choice of the Radiolabel 14
C is the label of choice for most drugs since it is stable biologically (when the right labeling position is chosen), the detection is comfortable1 and in case of combustion of samples the produced 14 CO2 can be nicely absorbed quantitatively. 3 H labeled drugs are easier to synthesize sometimes, but they are often less stable biologically or at least worse to predict in their biological stability. Because of its much higher specific activity, the 3 H-label is favorable in the case of high molecular weight drugs and/or very low doses. 35 S, 33 P, 125 J
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