Absorption, distribution, metabolism radiolabeled

Toxicokinetics studies are designed to measure the amount and rate of the absorption, distribution, metabolism, and excretion of a xenobiotic. These data are used to construct predictive mathematical models so that the distribution and excretion of other doses can be simulated. Such studies are carried out using radiolabeled compounds to facilitate measurement and total recovery of the administered dose. This can be done entirely in vivo by measuring levels in blood, expired air, feces, and urine these procedures can be done relatively noninvasively and continuously in the same animal. Tissue levels can be measured by sequential killing and analysis of organ levels. It is important to measure not only the compound administered but also its metabolites, because simple radioactivity counting does not differentiate among them. 

During the development of rivaroxaban 1, Pleiss et al. at Bayer Health Care prepared [14C]-radiolabeled rivaroxaban,22 which was required for clinical studies of drug absorption, distribution, metabolism, and excretion (ADME studies). The approach taken for the synthesis of l4C labeled rivaroxaban 38 relies on the previously reported synthesis. In the presence of EDC HCl and HOBT, 4- 4-[5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl -morpholin-3-one 22 was coupled with 5-chloro-2-thiophene [14C]-carboxylic acid 37 and was purified using chiral HPLC to afford the [l4C]-radiolabelled rivaroxaban 38 in 85% yield with high chemical and radiochemical purity and with an enantiomeric excess of > 99% ee (Scheme 5). Meanwhile, the metabolite M-4 of rivaroxaban (compound 39) was prepared from 5-chlorothiophenecarboxylic acid chloride 23 and [14C]glycine in 77% yield (Scheme 6). 

ADME Studies Absorption, distribution, metabolism, and excretion studies were conducted for 24,21,17, and 19 out of the 34 biopharmaceuticals, respectively. No radiolabeled proteins were used for 20, 2,1, and 13 out of the 34... 

For radiolabeled proteins,placement of the radiolabel is critical to the success of the study in regards to tissue distribution and other parameters related to absorption-distribution-metabolism-excretion or ADME characterization. 

The aim of this kind of study is to characterize the Absorption, Distribution, Metabolism and Elimination of the investigational product in humans (hADME study), following an administration of the compound in a radiolabeled form. The use of a radiolabel allows identifying metabolites, which were not known beforehand, and to characterize them. In addition, using a radiolabel is - in most cases - the only way to establish a complete balance of the drug and its metabolites, which is required to validate the completeness and predicitvity of the results. 

Sch 37224, 187, an efficient leukotriene release inhibitor185, has been radiolabelled in three steps giving 97% radiochemical purity and 27.3% radiochemical yield186 starting from U-[14C]-aniline as outlined in equation 73. 187 has been required to study the drug s absorption, distribution, metabolism and excretion. 

Absorption of orally administered cefquinome is poor, but absorption following intramuscular or subcutaneous administration proceeds relatively quickly. A small fraction of the intramammarily administered cefquinome is absorbed systemically. Distribution of cefquinome is not extensive following parenteral administration of radiolabeled cefquinome the highest activities were found in injection-site tissues, kidney, and liver. Excretion of parenterally administered cefquinome is predominantly renal, while intramammarily administered cefquinome is excreted mainly in milk. Cefquinome is metabolically quite stable. 

Following absorption, NMP is uniformly distributed throughout all major organs in the rat with a volume of distribution (about 0.71 kg ) that approximates total body water. In both the rat and man, NMP is eliminated primarily by metabolism to other compounds via a saturable process only about 2% of the absorbed NMP is excreted unchanged. The major metabolite is 5-hydroxy-NMP (50-70%) with lesser amounts of N-methylsuccinimde, 2-hy-droxy-N-methylsuccinimide, and possibly other unidentified metabolites. The half-life of NMP in plasma is 4h. Studies with radiolabeled NMP indicate the most of the radiolabel is excreted in the urine ( 95%), with lesser amounts in the feces ( 5%) and expired air ( 2%). Ongoing studies are investigating the use of 5-hydroxy-NMP as a urinary biomarker for human exposures to NMP. 

Mass Balance Studies. Pharmacokinetic mass balance studies apply unlabeled, stable isotopes or radiolabeled compounds to study the extent of absorption and first-pass metabolism, distribution, and excretion of a given compound. In the microdosing approach, a C-labeled compound is administered to human volunteers at doses from as low as one microgram blood, urine, and fecal samples are collected over time and analyzed for C content by accelerator mass spectroscopy to determine half-life, plasma AUC, and maximal concentration (Cmax)- However, these methods are not very popular even when very low doses of radioactivity are involved. Highly sensitive, and more readily available, tech-niques for separation and analysis (e.g., LC-MS, LC-MS/MS) are frequently used alternatives that enable pharmacokinetic investigations and metabolite profiling of nonradiolabeled compounds. 

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