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Halogen Labeled Compounds (F, Br, At, Cl) *
Published in Garimella V. S. Rayudu, Lelio G. Colombetti, Radiotracers for Medical Applications, 2019
Promising radiohalogenated agents are discussed with respect to their distribution, metabolism, or clinical utility. The discouraging results obtained from fluorinated amino acid, estrogen, and androgen analogs in general can be attributed to several factors: (1) species variations, (b) low specific activities, and (c) in vivo dehalogenation. The development of 18F-2-deoxy-2-fluoro-D-glucose as an imaging agent for brain and heart undoubtedly represents one of the most important achievements in the area of nuclear medicine. This demonstrated that a properly designed radiopharmaceutical not only can be useful as an organ imaging agent, but also can be used to study metabolism, or to measure other pharmacological parameters and physiological functions.
Environmental Toxins and Chronic Illness
Published in Aruna Bakhru, Nutrition and Integrative Medicine, 2018
Most of the phase I conversions involve oxidative processes. However, they can involve demethylation, hydroxylation, or dehalogenation (Lyon, 2013). Phase II reactions primarily result in conjugation of a xenobiotic or metal ion with a carrier molecule such as glutathione, cysteine, sulfate, glycine, glucuronic acid, thiosulfate, and glutamine (Croom, 2012; Lyon, 2013). However, another important phase II family of enzymes is the methyltransferase enzymes that add a methyl group to a compound. For almost all methylation reactions S-adenosylmethionine (SAM) is the methyl donor (Croom, 2012).
Radioimmunotherapy of Ovarian Cancer
Published in David M. Goldenberg, Cancer Therapy with Radiolabeled Antibodies, 1995
Anthony Maraveyas, Agamemnon A. Epenetos
This process comprises the “effective” half-life of the isotope. Antibodies are labeled with 131I usually by oxidizing a tyrosine residue.39 This is a quick and effective method but the procedure is susceptible to in vivo dehalogenation. In effect the measured half-life of an antibody labeled with iodine is the composite result of biological degradation and clearance of intact antibody, antibody fragments, and elemental iodine freed through the process of dehalogenation. Metal isotopes complexed to antibodies through chelating agents are not immune to similar processes. Free degradation products comprising the chelate ring or the chelate and a protein fragment are systematically produced and often further catabolized in the liver40 and kidneys. Isotope may also leach off the ring, and the elemental form may accrue in different tissues and may have a propensity for example, 90Y → bone 111In → liver.
Halogen bonding in halocarbon-protein complexes and computational tools for rational drug design
Published in Expert Opinion on Drug Discovery, 2019
Paulo J. Costa, Rafael Nunes, Diogo Vila-Viçosa
QM methods are more accurate in the description of both halogen bond energies and geometries. Indeed, apart from the highly computationally demanding CCSD(T) method [88], less expensive density functional theory (DFT) functionals such as ωB97X-D or M06-2X perform quite well [88–90] in non-covalent interactions such as halogen bonds. However, a practical application of such methods in halocarbon–protein complexes is not feasible due to the high computational cost, and, therefore, a few strategies were devised to tackle those large systems. For instance, QM/MM calculations, where the small molecule and a few residues are treated at the QM level while the remainder is calculated at the MM level, were used to study protein–ligand halogen-bonded complexes [15], showing that the strength of halogen bonds is comparable to classical hydrogen bonds, decreasing in the order H ≈ I > Br > Cl. In another study, QM/MM, coupled with PBSA calculations, was used to explain the basis for the inhibition of glycogen phosphorylase b by 5-halo-substituted glucopyranosyl nucleosides [91]. Nonetheless, QM calculations (MP2/aug-cc-pVDZ and HF/aug-cc-pVDZ) can be used to quantify the role of halogen bonding in protein–ligand binding and to estimate the relative contributions from electrostatic and dispersion forces [92] or possibly decipher the mechanism for dehalogenation by iodothyronine deiodinase, which seems dependent on halogen bonding [93].
Metabolism and disposition of lesinurad, a uric acid reabsorption inhibitor, in humans
Published in Xenobiotica, 2019
Vishal Shah, Chun Yang, Zancong Shen, Bradley M. Kerr, Kathy Tieu, David M. Wilson, Jesse Hall, Michael Gillen, Caroline A. Lee
From the AME study, total recovery over the 144-h study was nearly complete with dose recovered in both urine and feces. Most of the administered radioactivity was recovered within 72 h postdose (for a total of 87.3%) and urinary recovery was essentially complete by 24 h postdose (mean of 61.1% of the dose recovered). Elimination of lesinurad occurred both metabolically and renally in which CYP2C9 accounted for ∼50% and renal clearance was about 1/3 of total clearance with unchanged lesinurad accounting for 31.3% of the dose. The remainder of the radioactivity in the urine comprised of various metabolites (M1, M2, M3, M3b, M4, M16) of which oxidative metabolites, M3 and M4, accounted for 12.0% and 15.7%, respectively. In the feces, the 33.5% of the dose was largely composed of metabolites with lesinurad representing 1.5%. As the absolute bioavailability of lesinurad was nearly 100%, biliary elimination of lesinurad and/or intestinal secretion were likely explanations for the small percentage of radioactivity in the feces. Also, dibrominated metabolites of lesinurad were likely formed post-systemically via biliary elimination followed by reductive dehalogenation mediated by intestinal gut flora. Reduction via microsomal CYPs in the liver may also contribute to the production of circulating M2 (Kitamura et al., 1999). Reductive debromination of lesinurad could result in formation of a reactive intermediate, however, it was not tested based on the relatively low circulating M2 (0.3%) of M2 circulating and with no inherently apparent structural alerts.
Effect of molecular size on interstitial pharmacokinetics and tissue catabolism of antibodies
Published in mAbs, 2022
Hanine Rafidi, Sharmila Rajan, Konnie Urban, Whitney Shatz-Binder, Keliana Hui, Gregory Z. Ferl, Amrita V. Kamath, C. Andrew Boswell
Using antibodies labeled with radioactive metals through lysine-conjugated chelates, the in vivo fate of antibodies can be tracked due to the residualizing properties of the resulting metabolites. By pairing this approach with a non-residualizing iodine probe, we are able to determine the level of catabolism in tissues (Equation 6 and Figure 6). Several investigations including analyses of urine samples from clinical trials demonstrate that [111In]DOTA-ε-amino-lysine is the major radioactive catabolite of 111In-DOTA-modified antibodies56,57 and, when injected intravenously into mice, this catabolite rapidly cleared into the urine without kidney retention.57 Using in vitro studies, Shih and colleagues concluded that the prolonged retention of 111In relative to 125I is due to intracellular retention of catabolic products containing 111In, perhaps within lysosomes, not due to deiodination of iodine conjugates.58 These observations, along with the residualizing properties of [111In]DOTA-ε-amino-lysine, strongly favor the intracellular production and trapping of this catabolite within renal proximal tubules as opposed to redistribution of this catabolite from other tissues. Similar contrasts in uptake between 111In and 125I-labeled antibodies in receptor expressing tissues have been demonstrated in numerous in vivo studies.19,59–62 While dehalogenation has been a general concern for radioiodinated proteins in vivo, previous work has suggested little to no differences among an 125I-labeled IgG, F(ab’)2 and F(ab) when labeled by electrophilic addition to tyrosines (similar to the current method) versus labeling through lysines using a dehalogenase-resistant method.63