Syntheses, chemical labeled drugs

The simultaneous administration technique was used to study a 64-year-old man with a creatinine clearance of 79 mL/ min who was started on N-acetyl-procainamide (NAPA) therapy for ventricular arrhythmias (see Figure 4.4). The oral NAPA dose was 66% absorbed in this patient, compared to 91.6 9.2% when this method was used to assess NAPA absorption in normal subjects. Although this approach is ideally suited for studies of drug absorption in various patient populations, the required additional chemical synthesis of stable isotope-labeled drug and mass spec-trometric analysis of patient samples have precluded its widespread adoption. 

The various purity requirements should be considered when planning synthesis of the labeled drug. The Intended user should discuss this directly with the person or organization preparing the labeled drug. For example, chemical and radioIsomeric purities may be assured only by the method of synthesis. Determination of chemical purity may be possible only by the supplier who has access to the bulk of the labeled drug. 

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). 

By the use of radioactively labelled precursor chemicals, the cell s ability to synthesize macromolecules such as DNA, RNA, and proteins, after treatment with the drug, can be measured. A typical result is shown in Fig. 5, for exposure of the cells to the equivalent level of drug found in tumor tissue of a treated animal. The synthesis of new total DNA is selectively and persistently inhibited. Total RNA and protein syntheses are not markedly affected until much higher drug-dose levels, which are frankly toxic to... 

I believe that this book is extremely informative for researchers who want to take advantage of the use of fluorine in biomedical research such as rational drug design, theory and synthesis, the use of fluorine labels for chemical and structural biology, metabolism and biodistribution studies, protein engineering, clinical diagnosis, etc. This book will serve as an excellent reference book for graduate students as well as scientists at all levels in both academic and industrial laboratories. 

Radiochemical purity. The radiochemical purity of a radiopharmaceutical is defined as the fraction of the total activity in the desired chemical form in the sample. These impurities arise from incomplete labehng, breakdown of the labeled products over time due to instabihty, and introduction of extraneous labeled ingredients during synthesis. These impurities cause altered in vivo biodistribution after administration, resulting in an unnecessary radiation dose to the patient. For these reasons, the United States Pharmacopea (USP) and the United States Food and Drug Administration have set limits on the impurities in various radiopharmaceuticals, and these limits must not be exceeded in clinical operations. 

---