Metabolites human

Perfused rat liver rapidly converts 4-m thyI-5-/3-chloroethy]thiazole to 2-hydroxy -4-methylthiazol-5-y) acetic acid (40. 41). Finally, tw o new human metabolites of chlormethiazole have been isolated and identified by mass spectra as 2-hydroxy-4-methyl-5-/S-chloroethylthiazole and 2-hydroxy-4-methyl-5-ethylthiazole (42). 

M. A. J. Bayliss, P. R. Baker and D. Wilkinson, Determination of the two major- human metabolites of tipredane in human urine by liigh performance liquid cliromatogr-aphy with column switching , J. Chromatogr. 694 199-209 (1997). 

Considerable effort is often required to prepare sufficient quantities of key mammalian metabolites of drug candidates for biological activity evaluation or for use as analytical standards. The new regulatory guidance in drug development [5] will certainly lead to more emphasis on key human metabolite characterization. Microbial bioreactors can be used for... 

Otey, C.R., Bandara, G., Lalonde, J.L. et al. (2006) Preparation of human metabolites of propranolol using laboratory-evolved bacterial cytochromes P450. Biotechnology and Bioengineering, 93, 494 499. 

Li, W., Josephs, J.L., Skiles, G. and Humphreys, W.G. (2008) Metabolite generation via microbial biotransformation with actinomycetes rapid screening methods and synthesis of important human metabolites of two development stage compounds, BMS-587101 and dasatinib. Drug Metabolism and Disposition The Biological Fate of Chemicals, 36, 721-730. 

Freitag, D.G., Foster, R.T., Coutts, R.T. et al. (1997) Stereoselective metabolism of rac-mexiletine by the fungus Cunninghamella echinulata yields the major human metabolites hydroxymethylmexiletine and p-hydroxymcx-iletine. Drug Metabolism and Disposition The Biological Fate of Chemicals, 25, 685-692. 

In humans, metabolites of acrylonitrile have been identified in urine following occupational exposure (assumed to be by the inhalation route), and also in controlled exposure studies. Metabolites identified in humans were the same as those in animals (Jakubowski et al. 1987 Sakurai et al. 

The high amounts in which these substances are consumed and produced have conferred illicit drugs and their human metabolites a pseudo-persistent character in the environment. Like over-the-counter and prescribed pharmaceuticals, illicit drugs are metabolized after consumption and different proportions of the parent compound and metabolic by-products are excreted via urine or feces and flushed into the sewage system toward wastewater treatment facilities, if existing. However, these substances are poorly or incompletely removed by conventional waste-water treatment processes [2, 3]. As a consequence, illicit drugs and metabolites are continuously introduced via wastewater treatment plant (WWTP) effluents into the aquatic media. In fact, this constitutes the main route of entry of this type of compounds into the environment as direct disposal is unlikely. 

R.B. Desai, M.S. Schwartz and B.K. Matuszewski, The identification of three human metabolites of a peptide-doxorubicin conjugate using HLPC-MS-MS in positive and negative ionization modes. J. Chromatogr. Sci. 42 (2004) 317-322. 

K. K. Wong, N. Kucharczyk, R. D. Sofia, Isolation and Identification of 3-Carbamoy-loxy-2-Phenylpropionic Acid as a Major Human Metabolite of Felbamate , Drug Metab. Dispos. 1993, 21, 710-716 V. E. Adusumalli, K. K. Wong, N. Kucharczyk, R. D. Sofia, Felbamate in vitro Metabolism by Rat Liver Microsomes , Drug Metab. Dispos. 1991, 19, 1135-1138. 

Escher BI, Bramaz N, Richter M, Lienert J (2006) Comparative ecotoxicological hazard assessment of beta-blockers and their human metabolites using a mode-of-action-based test battery and a QSAR approachf. Environ Sci Technol 40 7402-7408... 

Postigo C, Alda MJLd, Barcelo D (2008) Analysis of drugs of abuse and their human metabolites in water by LC-MS(2) a non-intrusive tool for drug abuse estimation at the community level. TRAC-Trends Anal Chem 27(11) 1053-1069... 

In general, the expected clinical route of administration should be used when feasible. Regardless of route, exposure to the parent compound and its major metabolites should be similar or greater than that observed in humans. Because safety pharmacology studies are carried out before human studies are initiated, this may have to be inferred from information derived from in vitro studies, for example, with human hepatocytes and/or from information from similar compoimds that have been used in humans. In some cases, early low-dose human studies may show that significant metabolites are formed in humans but were not formed in the animals used in safety pharmacology studies. In these circumstances, further studies will be needed in animals using isolated or chemically synthesised human metabolites. 

The lARC has concluded that there is limited evidence for carcinogenicity to animals and inadequate evidence for humans. ACGIH considers PBNA to be a suspected human carcinogen because P-naphthylamine is both an impurity and a human metabolite of PBNA. ... 

Another human metabolite, quercetin-4 -glucuronide, inhibits xanthine oxidase in vitro at a concentration in plasma that on normal diets can realistically be approached (A, = 0.25 Various mammalian conjugates of quercetin suppress the formation of... 

Mueller SO, Simon S, Chae K, Metzler M, Korach KS. Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor (alpha) and ER(beta) in human cells. Toxicol ScL 81, 530-531, 2004. 

Generation of potential human metabolites for structural identification prior to administration of the drug candidate to humans can be performed with either cDNA-expressed enzymes or tissue fractions. This allows identification of potential human metabolites and development of appropriate analytical methods prior to clinical trials. Generation and identification of pharmacologically active human metabolites early in the development process can be beneficial for obtaining appropriate patent protection. 

In vitro systems containing human xenobiotic-metabolizing enzymes can provide qualitative data, such as the human metabolites which may be produced in vivo and which enzymes are capable of producing these metabolites. When comparing quantitative aspects of metabolism among different cytochrome P450 forms in a cDNA expression system, the data can be interpreted in two contexts ... 

The principal human metabolite having been identified as the aryl morphohnol 2, subsequent analysis confirmed that 2 was a mixture of (S,S)- and (R,R)- enantiomers, 2a and 2b respectively. Later studies confirmed that the (R,R)-enantiomer 2b was the major metabolite typically 90-95% compared to 5-10% of the (S,S)-enantiomer 2a (radafaxine free base), while the amino alcohol 3 was formed as an approximately 1 1 mix of the erythro and threo isomers. 

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