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Disposition and Metabolism of Drugs of Dependence
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
dl-α -Acetyl methadol was synthesized252,272 in 1948 to 1949. The presence of two asymmetric carbon atoms in the molecule results in two pairs, α and β of diastereoisomers. The levo isomer is derived from d -methadone and dextro isomer from l -methadone. The α-l -acetyl methadol hydrochloride m. 215°C is soluble in water and is a potent analgesic structurally related to methadone with a prolonged duration of action providing practical therapeutic advantages over methadone in treatment of heroin addicts;273 thus a patient on a 50 mg daily methadone regimen could be maintained on 40 to 60 mg of dl-α-acetyl methadol three times a week. The oral analgesic dose is 7.5 to 10 mg.
Principles
Published in Sarah Armstrong, Barry Clifton, Lionel Davis, Primary FRCA in a Box, 2019
Sarah Armstrong, Barry Clifton, Lionel Davis
Optical isomers (enantiomers) are compounds that are mirror images of each other around a central atom (chiral centre) Originally classified according to their ability to rotate the plane of polarized light in opposite directions (levo/dextro isomers)This classification has been superseded by the R (rectus)/S (sinister) system, which describes the configuration of the atoms around the chiral atom according to the molecular weights of the other atomsA racemic mixture contains equal amounts of the two isomers and consequently has no optical activityDiastereoisomers have more than one chiral centre and are not mirror images of each other
Pitfalls and Practical Solutions
Published in Joseph Chamberlain, The Analysis of Drugs in Biological Fluids, 2018
A particular type of artifact formation is in the racemization, or inversion of optically active compounds. Some drugs are considered to racemize so easily that it is accepted that nonchiral methods are adequate to measure their levels in biological fluids. However, where the racemate is dosed and it is desired to follow the true concentration of the separate enantiomers, then it is essential to ensure no artifactual racemization occurs, either in the extraction procedure or in the derivatization. Wright and Jamali1494 studied the potential of derivatization with ethylchlorformate for stereochemical conversion during the process of preparing diastereoisomers of several anti-inflammatory drugs with R-(+)-_-phenylethylamine or L-leucinamide. Although they concluded that conversion could occur, the degree of conversion was small enough in the assay conditions not to contribute a significant error to the results.
In vitro metabolism assessment of thiacloprid in rainbow trout and rat by LC-UV and high resolution-mass spectrometry
Published in Xenobiotica, 2021
Jose Serrano, Richard C. Kolanczyk, Brett R. Blackwell, Barbara R. Sheedy, Mark A. Tapper
The accurate mass for THI and metabolites TM1, TM2 and TM3, as determined from LC-HR-MS experiments (M + H), was 253.10226, 228.03574, 126.05475 and 128.02740 Da respectively, with all detected structures within a mass error <7 ppm (see Supplemental Tables S5 and S6). Specifically, LC-MS mass chromatograms of THI slice exposures showed the presence of two isomers for both TM1 and TM2 corresponding to the Z-/E-diastereoisomers of TMI (retention times of 1.189 and 1.437 min, respectively), and the enol-/aldehyde-tautomers of TM2 (0.917 and 1.233 min, respectively; Supplemental Table S6). Diastereoisomers are stereoisomers of the same constitution, but the molecules do not have a mirror-image relationship and have different physical and chemical properties. On the other hand, tautomers are molecules with the same molecular formula but different connectivity that are formed in common acid- or base-catalyzed processes.
Absorption, distribution, metabolism and excretion of darolutamide (a novel non-steroidal androgen receptor antagonist) in rats
Published in Xenobiotica, 2020
Päivi Taavitsainen, Hille Gieschen, Timo Korjamo, Marja Kähkönen, Chira Malmström, Olaf Prien, Michael Niehues, Steffen Sandmann, Wiebke Janssen, Mikko Koskinen
One interesting feature of darolutamide PK is the ability of the two diastereoisomers to interconvert metabolically. Both in vitro and in vivo results show that after dosing of one individual diastereoisomer, the other diastereoisomer also appears. This interconversion takes place through the keto-metabolite, as established by incubating keto-darolutamide in hepatocytes. Interconversion occurred rapidly in vivo in rats, the other diastereoisomer being detected within 15 min post-dosing. Similar diastereoisomer–plasma ratios were observed with single dose; and were maintained at high doses. Nevertheless, there was a tendency towards a slight preference for (S,S)-darolutamide after repeated dosing. This is against the observation that the intrinsic rate of metabolism is likely higher for (S,S)- than (S,R)-darolutamide in rats (Figure 6(A)). However, reduction of keto-darolutamide seems to favour the formation of (S,S)-darolutamide, resulting in increased exposure in vivo (Figure 6(B)). Quantitative mechanistic assessment of the interconversion deserves further study, as the current in vitro hepatocyte studies qualitatively support the in vivo results.
D-Alanine Is Reduced by Ocular Hypertension in the Rat Retina
Published in Current Eye Research, 2020
Takashi Kanamoto, Hiroaki Sakaue, Yasushi Kitaoka, Ryo Asaoka, Kei Tobiume, Yoshiaki Kiuchi
The retinas were carefully isolated from enucleated eyes in PBS and the amino acids were analyzed by HPLC, as previously described.19 Briefly, the homogenized retina was hydrolyzed with gas-phase 6 N HC1 for 7 h at 108°C. After hydrolysis, the hydrolysate was evaporated to dryness under reduced pressure. The hydrolyzed samples were dissolved in 0.1 M borate buffer (pH 10.4) and were incubated briefly with o-phthalaldehyde (OPA) (Sigma-Aldrich, St. Louis, MO) and n-tertbutyloxycarbonyl-L-cysteine (Boc-L-Cys) to form diastereoisomers. The residual amino acids were analyzed by RP-HPLC with a Nova-Pak ODS column (3.9 mm × 300 mm; Waters, Tokyo, Japan) using fluorescence detection (Ex/Em. 344/433). Elution was carried out with a linear gradient of 5-47% acetonitrile plus 3% tetrahydrofuran in 0.1 M acetate buffer (pH 6.0) in 120 min at a flow rate of 0.8 ml/min, at 30°C.