Metabolic fate

The metabolic fate of l-(4-methoxy-6-methyl-2-pyrimidinyl)-3-methyl-5-methoxy-pyrazole, mepirizole, has been investigated in rats, rabbits and man. Three metabolites, (751), (752) and (753), were identified in human urine (76CPB804). 

Another widely used approach to the elucidation of metabolic sequences is to feed cells a substrate or metabolic intermediate labeled with a particular isotopic form of an element that can be traced. Two sorts of isotopes are useful in this regard radioactive isotopes, such as and stable heavy isotopes, such as or (Table 18.3). Because the chemical behavior of isotopically labeled compounds is rarely distinguishable from that of their unlabeled counterparts, isotopes provide reliable tags for observing metabolic changes. The metabolic fate of a radioactively labeled substance can be traced by determining the presence and position of the radioactive atoms in intermediates derived from the labeled compound (Figure 18.13). 

In view of the increasing number of industrial applications of organ-otins, which are described in the next section, a knowledge of their metabolic fate in mammals is obviously of considerable importance. 

A knowledge of the metabolic fate of a particular drug, both in terms of the identification and quantification of the metabolites, is necessary not only to ensure that its use will not cause more problems than the medical condition it is designed to alleviate but, from the drug company s perspective, to facilitate the design of more effective drugs. 

On the other hand, the scrambled model of carbon sourcing does not seem to be applicable when we consider the metabolic fate of fatty acids. We find that there are partial barriers to the movement of FA-derived carbon atoms into the synthesis of proteins. This partial restriction leads us to expect a trophic level effect in the fractionation between collagen and bone apatite or respired CO2 of which apatitic carbonate is a sample. The magnitude of the fractionation depends on two separate fractionation factors which cannot be disentangled by analyses of bone samples alone. 

Miyamoto J, Sato Y, Kadota T, et al. 1963a. Studies on the mode of action of organophosphorus compounds. Part I. Metabolic fate of P32 labeled sumithion and methylparathion in guinea pig and white rat. Agric Biol Chem 27 381-389. 

In Chapter 2, the fate of organic pollutants in living organisms and the processes involved were described. In this section, the relationship between the properties of chemicals and the operation of those processes will be briefly reviewed. Many examples of the influence of properties of a chemical on its own metabolic fate will be encountered in Part 2 of this book. 

METEOR Rule-based Metabolite prediction software Predicts the metabolic fate of chemicals Displays results as a metabolic tree. User can filter results for likely metabolites. Links directly to MetaboLynx for analysis of mass spectrometry data www.lhasalimited.org... 

Coe and Bessell and coworkers studied the metabolic fates of 2-deoxy-2-fluoro-D-glucose (2DFG) and related compounds by using yeast hexokinase (as a model for mammalian hexokinase), and determined the kinetic constants K and V ) of the Michaelis-Menten equation D-glucose 0.17 (K in mAf)> 1 00 (relative value, D-glucose taken as 1) 2DG 0.59 0.11, 0.85 2DFG 0.19 0.03, 0.50 2-deoxy-2-fluoro-D-mannose (2DFM) 0.41 0.05, 0.85 2-deoxy-2,2-difluoro-D-nraZ>//Jo-hexose... 

C]-FlAC was synthesized from [2- C]cytosine in the general manner used for unlabeled 748 (FIAC), and its metabolic fate in mice was studied. The compound (after i.v. injection) was deaminated by cytosine nucleoside deaminase and appeared as [2- C]-FIAU in plasma, as confirmed by experiments on rats having a very low level of the deaminase, and by treatment with tetrahydrouridine, a nucleoside deaminase inhibitor. This was further confirmed by the use of purified human deoxycytidine deaminase. It was... 

Figure 25-3. Metabolic fate of chylomicrons. (A, apolipoprotein A B-48, apolipoprotein B-48 , apolipoprotein C E, apolipoprotein E HDL, high-density lipoprotein TG, triacylgiycerol C, cholesterol and cholesteryl ester P, phospholipid HL, hepatic lipase LRP, LDL receptor-reiated protein.) Only the predominant lipids are shown.

Distribution and Metabolic Fate—In Vivo and In Vitro Studies... 

SETCHELL K D, ZIMMER-NECHEMIAS L, CAI J and HEUBI J E (1998) Isoflavone Content of infant formulas and the metabolic fate of these phytoestrogens in early life. Am. 1 Clin Nutr. 68 (6 Suppl) 1453S-1461S. 

Heim K, 1 Schuphan, B Schmidt (1994) Behaviour of [ " C]-4-nitrophenol and [ " C]-3,4-dichloroaniline in lab sediment-water systems. 1. Metabolic fate and partitioning of radioactivity. Environ Toxicol Chem 13 879-888. 

Examples of PLC with autoradiography detection include the published studies on labeling of l- H-PAF-aceter [25] diazinon and related compounds from plant material [26] metabolic fate of triamcinolone acetonide in laboratory animals [27] synthesis of 4-S-cysteaminyl-[U- " C]phenol antimelanoma agent [28] radiolabeled... 

FAAH was originally purified and cloned from rat liver microsomes and is able to catalyse the hydrolysis of anandamide and 2-AG, in addition to other long-chain fatty acid amides [25]. Studies into the structure and role of this enzyme have generated interest in the potential therapeutic applications of FAAH inhibitors [26-28]. FAAH knock-out mouse brains contained 15-fold higher levels of anandamide than their wild-type counterparts and these animals have also been shown to be more responsive to exogenously administered anandamide [29]. These animals also showed a reduced response to painful stimuli, supporting the hypothesis that FAAH inhibition may provide novel analgesics. Levels of 2-AG were not elevated in the FAAH knock-out animals, apparently due to the existence of alternative metabolic fates for this compound [30]. 

Seasonal variations in the metabolic fate of adenine nucleotides prelabelled with [8—1-4C] adenine were examined in leaf disks prepared at 1-month intervals, over the course of 1 year, from the shoots of tea plants (Camellia sinensis L. cv. Yabukita) which were growing under natural field conditions by Fujimori et al.33 Incorporation of radioactivity into nucleic acids and catabolites of purine nucleotides was found throughout the experimental period, but incorporation into theobromine and caffeine was found only in the young leaves harvested from April to June. Methy-lation of xanthosine, 7-methylxanthine, and theobromine was catalyzed by gel-filtered leaf extracts from young shoots (April to June), but the reactions could not be detected in extracts from leaves in which no synthesis of caffeine was observed in vivo. By contrast, the activity of 5-phosphoribosyl-1-pyrophosphate synthetase was still found in leaves harvested in July and August. 

The purpose of this paper is to give some of the results obtained in a study of the antidotal action of barbiturates in chlordan poisoning, and of the metabolic fate of chlordan. 

STOHLMAN AND SMITH—TOXICOLOGICAL ACTION AND METABOLIC FATE OF CHLORDAN... 

The metabolic fate of chlordan was studied in rabbits by analysis of the relative chlorine content of chlordan added to normal rabbit s urine and of the chlorine content of the urinary excretory product. The method of analysis was similar to the one previously used (, 4) In addition, hydrolysis of chlordan and of the urinary excretory products was carried out by adding solid sodium hydroxide to saturation to a 10-ml. solution of these substances in hot absolute ethyl alcohol. The mixture was refluxed for 3 hours in a round-bottomed flask immersed in boiling water and the amount of inorganic chlorine determined. Hydrolysis was similarly carried out with solutions of the respective substances in aqueous sodium hydroxide. 

Bollinger JN. 1970. Metabolic fate of mineral oil adjuvants using 14C-labeled tracers. I. Mineral Oil. J Pharm Sci 59 1084-1088. 

Less explored is the role and metabolic fate of 2-AG. It is possible that in many tissues, 2-AG is only an intermediate of a signaling pathway that generates 1,2-diacylglycerol and arachidonic acid, two well-known signaling molecules. In the brain however, 2-AG may have regulatory roles, since it escapes immediate metabolism and accumulates in response to stimuli-generated Ca2+ surges (Stella, 1997). These differences may arise... 

Niclosamide is not significantly absorbed from the gastrointestinal tract [94], However, no specific data for pharmacokinetic parameters for niclosamide is available in literature. The metabolic fate of the small amount of drug that is absorbed is unknown but presumably it is metabolized in the liver, possibly to less active forms. 

Metabolic fate of irinotecan in humans correlation of glucuronidation with diarrhea. Cancer Res 1994 54 3723-3725. 

Figure 14.4 Schematic diagram comparing the bulk and molecular schemes for the metabolic fate of macronutrient components between diet and consumer tissues...

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