14C-labeled drug

This potent inhibitor of cholesterol biosynthesis has been synthesized178 by one-pot esterification of the alcohol 210 with the acid chloride of 2,2-dimethylbutanoic[l-14C] acid, obtained by carbonation of the Grignard reagent prepared from 2-chloro-2-methylbutane (equation 74). Desilylation of 211 afforded [14C]simvastatin 209 in 29% radiochemical yield from 14C-labelled C02. This 14C-labelled drug was needed for elucidation of its metabolic fate in experimental animals. 

Gamer RC, Barker J, Flavell C et al. (2000) A validation study comparing accelerator MS and liquid scintillation counting for analysis of 14C-labelled drugs in plasma, urine and faecal extracts. J Pharm Biomed Anal 24 197-209 Hayakawa H, Fukushima Y, Kato H et al. (2003) Metabolism and disposition of novel des-fluoro quinolone garenoxacin in experimental animals and an interspecies scaling of pharmacokinetic parameters. Drug Metab Dispos 31 1409-1418... 

The list of AMS applications in pharmaceutical research continues to grow since its introduction in 1990s. With subattomole sensitivity, AMS is an ideal analytical technique for bioavailability studies using the isotope methodology with 14C-labeled drug, since it has extremely low natural abundance (10 n%) [54,55], When AMS is... 

The negligible intestinal absorption of rifaximin was subsequently confirmed with the use of the labeled drug. After oral administration in rats the total radioactivity present in plasma was found to be no more than 0.1 and 2% of the administered dose after the intake of 3H-labeled [99] and 14C-labeled [59] compound, respectively. 

C-F-IMF, 170, containing famesyl moiety labelled with 14C, has been obtained involving the synthesis of 14C-labelled famesol [14C-F, 173] from ketone 174 (equation 60). 169 and 170 have been synthesized in order to clear the pharmacokinetic profile of these drugs in vivo and in vitro. 

The ability of a tumor cell to manufacture proteins is a result of intact DNA, RNA and biochemical intracellular mechanisms. Interference with any one of these structures or processes will result in the inability of the cell to produce required proteins. Hence, quantitation of tumor cell protein synthesis over a period of time may constitute a marker allowing determination of the efficacy of a macromolecular drug conjugate. The technique is based on the fact that decreased cell viability in the presence of radiolabeled amino adds correlates to a decrease in radioactivity relative to a control cell population. For example, 3H-leucine [175, 208], a mixture of [14C]-labeled amino acids [205], and 75Se-lenomethionine [54, 209] have been used to evaluate the activity of conjugates. 

The disposition of this new 14C-labelled anti-inflammatory drug, 271, and its metabolite, 272, in 4 volunteers has been studied285. The elimination half-life of 271 was about... 

Gamer, R. C., Goris, I., Laenen, A. A., Vanhoutte, E., Meuldermans, W., Gregory, S., Gamer, J. V., Leong, D., Whattam, M., Calam, A., and Snel, C. A. (2002). Evaluation of accelerator mass spectrometry in a human mass balance and pharmacokinetic study—Experience with 14C-labeled (R)-6-[amino(4-chlorophenyl)(l-methyl-l //-imidazol-5-yl)methyl -4-(3-chlorophenyl)- l-methyl-2(17/ i-quinolinone (R115777), a famesyl transferase inhibitor. Drug Metab. Dispos. 30 823-830. 

To measure the transport of drugs across the BBB in vitro 2.5 iCi of 3H-labelled drug and 14C-sucrose are applied to each Transwell (in case of 14C-labeled substances, permeability studies are performed with 3H-sucrose). This concentration is high enough to ensure sufficient excess to neglect the decrease of tracer in the donor (apical) compartment during the experiments. Volumes of 1.5 ml in the donor (apical) and 2.5 ml in the acceptor (basolateral) compartment avoid hydrostatic pressure. After addition of the radiolabeled compound, samples of 50 til are taken in duplicate from the basolateral acceptor compartment every 20 min and replaced by 100 xl of fresh assay medium. Cells are kept under culture conditions during the whole transport experiment. Radioactivity is measured after addition of liquid scintillation cocktail in a counter. 

Three healthy male beagles receive an intravenous dose into a jugular vein or into the vena cephalica antebrachii (typically 1-5 mg/kg b.w.). After a wash out period dependent on the duration of excretion of the drug/metabolites (typically 4 weeks at minimum), the same animals are dosed orally by using a stomach tube (typical dose 10 mg/kg b.w.). Normally, 5-10 MBq/animal is a sufficient radioactive dose for a 14C-label, in case of 3H about 50 MBq/animal could be used. Up to 168 h after administration, blood, urine and feces are collected. At each collection time about 3.5 mL of blood are taken for radioanalysis (2-3 aliquots) and for processing plasma for subsequent radio- and bioanalysis in plasma (also 2-3 aliquots each). The plasma is aliquoted immediately after centrifugation without warm-up. At a few preselected time points additional blood is collected for metabolite investigations (about 5 mL). 

HMR 1556 was a drug candidate developed for treatment of hypertension. It was 14C-labeled and investigated in a rat mass balance study to determine the pattern and rate of excretion, the residual concentrations at the end of the study 168 h after administration and the mass balance following oral and intravenous route of administration. 

The radiolabeled drug is administered to 54 healthy male Sprague Dawley rats (weighing about 200 g corresponding to an age of 6-10 weeks). 27 animals receive an oral dose by stomach tube (typically 10 mg/kg bw) and 27 animals receive an intravenous dose into a tail vein (typically 1-5 mg/kg total radioactivity of about 2 MBq/animal in case of 14C-label). 

Recent drug assay development involved LC-MS methods (Caubet et al. 2004 Kanazawa et al. 2000). A less practical breath test, using 13C or 14C labeled caffeine, can also be used (Kalow and Tang 1991). 

Rifampicin was first shown by Hartmann et al. 54 to have a specific inhibitory effect on RNA polymerase from E. coli. Later, other active ansamycins were found and RNA polymerases from a large variety of bacteria other than E. coli proved to be sensitive to the drug. More recently, an RNA polymerase from E. coli containing only one subunit and probably involved in the initiation of DNA replication (dna G gene product) has been shown to be resistant to rifampicin5 s This holds true also for the various mammalian RNA polymerases. In contrast to non-specific inhibitors of transcription such as actinomycin and mitomycin, rifampicin interacts specifically with the bacterial enzyme itself. With the aid of 14C-labelled rifampicin it could be shown that the drug forms a very stable complex with the enzyme in a molar ratio of 1 1S6> 57 The dissociation constant of this complex is 10-9 M at 37 °C and... 

Compound 52 an effective anti-hypertensive drug, has been synthesized44b for biotransformation studies from p-chlorobenzoic acid-carbonyl-14C (53) in three steps modifying the methods of Sturm45, Hoefle46 and coworkers (equation 23). The intermediate 4-chloro-3-sulphamoylbenzoic acid-carbonyl-14C (54) with thionyl chloride yielded the acid chloride 55, which with 2-amino-3aa, 4a,5,6,7aa-hexahydro-4,7-methano-isoindoline gave the carbonyl-14C labelled compound 52. The UV spectra of 52 and of the unlabelled 52 as well as the Rf value on TLC of the single radioactive peak and of the fluorescent spot of unlabelled authentic specimen of 52 coincided. 

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