Major metabolic pathway

These few examples are only an introduction we li look at several of the major metabolic pathways in much more detail in Chapter 29. The bottom line is that you haven t seen the end of carbonyl-group chemistry. A solid grasp of carbonyl-group reactions is crucial to an understanding of biochemistry. 

E Biologically important molecules and mechanisms have received particular attention in this edition. Many reactions now show biological counterparts to laboratory examples, many new problems illustrate reactions and mechanisms that occur in living organisms, and enhanced detail is given for major metabolic pathways. 

A new tool for computational ADME/Tox called MetaDrug includes a manually annotated Oracle database of human drug metabolism information including xenobiotic reactions, enzyme substrates, and enzyme inhibitors with kinetic data. The MetaDrug database has been used to predict some of the major metabolic pathways and identify the involvement of P450s [78]. This database has enabled the generation of over 80 key metabolic... 

Figure 15-7. Intracellular location and overview of major metabolic pathways in a liver parenchymal cell. (AA —metabolism of one or more essential amino acids AA <->, metabolism of one or more nonessential amino acids.)...

PBPK models have also been used to explain the rate of excretion of inhaled trichloroethylene and its major metabolites (Bogen 1988 Fisher et al. 1989, 1990, 1991 Ikeda et al. 1972 Ramsey and Anderson 1984 Sato et al. 1977). One model was based on the results of trichloroethylene inhalation studies using volunteers who inhaled 100 ppm trichloroethylene for 4 horns (Sato et al. 1977). The model used first-order kinetics to describe the major metabolic pathways for trichloroethylene in vessel-rich tissues (brain, liver, kidney), low perfused muscle tissue, and poorly perfused fat tissue and assumed that the compartments were at equilibrium. A value of 104 L/hour for whole-body metabolic clearance of trichloroethylene was predicted. Another PBPK model was developed to fit human metabolism data to urinary metabolites measured in chronically exposed workers (Bogen 1988). This model assumed that pulmonary uptake is continuous, so that the alveolar concentration is in equilibrium with that in the blood and all tissue compartments, and was an expansion of a model developed to predict the behavior of styrene (another volatile organic compound) in four tissue groups (Ramsey and Andersen 1984). 

These studies on NPYR are typical of the state of the art in cyclic nitrosamine metabolism ai d activation. The major metabolic pathways have been rather well characterized, but data on the relationship of these pathways to carcinogenesis are limited. This is especially true of the organospecific effects of NPYR and the other cyclic nitrosamines. For example, the main target organs for NPYR in the Syrian golden hamster are the trachea and nasal cavity rather than the liver. This is in spite... 

Aiming at the feasibility study of such type of asymmetric decarboxylation, we screened microorganisms which are able to grow on the medium containing tropic acid as the sole source of carbon. It is expected that at least one of the major metabolic pathway of tropic acid is the oxidation of the hydroxyl group followed by decarboxylation and further oxidation of the resulting aldehyde (Fig. 20). If... 

The major metabolic pathways of flutolanil in plants are para-hydroxylation of the aniline ring and hydr-oxylation of the isopropoxy side chain. For potatoes, flutolanil anddesisopropyl-flutolanil (M-4) are selected as the target analytes. For rice plant, other metabolites containing 2-(trifluoromethyl)benzanilide moiety are also selected as the target analytes. For soil and water samples, flutolanil is selected as the only target analyte. 

The major metabolic pathway for hydrogen sulfide in the body is the oxidation of sulfide to sulfate, which is excreted in the urine (Beauchamp et al. 1984). The major oxidation product of sulfide is thiosulfate, which is then converted to sulfate the primary location for these reactions is in the liver (Bartholomew et al. 1980). 

The major metabolic pathway of hydrogen sulfide is the oxidation of the sulfide to sulfate in the liver (Beauchamp et al. 1984). Methylation also serves as a detoxification route. Hydrogen sulfide is excreted primarily as sulfate (either as free sulfate or as thiosulfate) in the urine. 

The major metabolic pathways of the TCAs are demethylation, hydroxyla-tion, and glucuronide conjugation. Metabolism of the TCAs appears to be linear within the usual dosage range, but dose-related kinetics cannot be ruled out in the elderly. 

Pharmacokinetic parameters and major metabolic pathways of antipsy-chotics are summarized in Table 71-2. 

Figure 7 shows the major metabolic pathway of triprolidine hydrochloride as determined in a study of 14C labelled triprolidine hydrochloride in guinea pigs.6 Triprolidine is converted to metabolite I by liver microsomes. Metabolite I is converted to metabolite II which is the major metabolite found in guinea pig urine. 

The major metabolic pathway of carbamazepine is an example of this oxidation as shown in Figure 4.73. The usual bond angle of a sp3-hybridized carbon is 109°, but it is constrained to be 60° in an epoxide making epoxides reactive. This reactivity varies significantly depending on the structure of the epoxide, and this will be discussed further in Chapter 8. The epoxide of carbamazepine is relatively unreactive and easy to isolate. 

Cyanide is metabolized in the body by two metabolic pathways that have been identified (Ansell and Lewis 1970). The first and major metabolic pathway involves the transfer of sulfane sulfurs from a donor to cyanide to yield thiocyanate (see Section 2.3). The reaction employs the enzyme rhodanese as a... 

Fariss MW, Blanke RV, Saady V, et al. 1980. Demonstration of major metabolic pathways for chlordecone (Kepone) in humans. Drug Metab Dispos 8 434-438. 

Levels of Significant Exposure to Di-n-octylphthalate - Oral 2-2. Major Metabolic Pathway of Di-n-octylphthalate 2-3. Existing Information on Health Effects of Di-n-octylphthalate 5-1. Frequency of NPL Sites with Di-n-octylphthalate Contamination... 

There were also less concrete considerations. In the early 1950s glycogenolysis was still believed to be completely reversible. UTP dependency and the glycogen synthase reactions had not yet been discovered nor had phosphofructokinase been shown to act irreversibly. The mechanism of protein synthesis was still a mystery. Laboratories studying proteolysis had shown that the peptide bond could be resynthesized by peptidases, although under very restricted conditions. Reversibility seemed to be an accepted property of the major metabolic pathways. 

James, M. 0. and Bend, J. R. Taurine conjugation of 2,4-dichlorophenoxyacetic acid and phenylacetic acid as a major metabolic pathway in two marine species. Xenobiotica (1976)... 

Antibacterial sulfonamides contain two N-atoms, the sulfonamido (N1) and the para primary amino (N4). The sulfonamido group, in contrast to a carboxamido group, is chemically and metabolically stable. In other words, hydrolytic cleavage of sulfonamides to produce a sulfonic acid and an amine has never been observed. We, therefore, focus our discussion on the primary amino group, acetylation of which is one of the major metabolic pathways for some sulfonamides. Hydrolysis of the N4-acety luted metabolites back to the parent sulfonamide can occur in the liver, kidney, and intestinal tract. The reaction is strongly influenced by the structure of the parent amine e.g., N4-acetylsulfisoxazole (4.121) was deacetylated by intestinal bacteria whereas /V4-acctyIsulI anilamide (4.122) under identical conditions was not [78][79],... 

Marked species differences in hydrolytic cleavage were also observed for pranlukast (4.160), a leukotriene receptor antagonist. In rats, amide hydrolysis represented a major metabolic pathway, whereas, in humans, it was apparently absent. Investigations with purified enzymes showed that pranlukast... 

Turning to tetrahydrophthalimide derivatives, we find the pyrethroid insecticide tetramethrin (4.191). In the rat, a major metabolic pathway involves... 

The phthalimido moiety can be found in a number of xenobiotics, but the relative importance of its hydrolysis varies widely. For example, hydrolysis was a major metabolic pathway in the rat for /V-(2-acctylphenyl)phthalimidc (4.194) [121]. 

One should not conclude from the above that the glutarimide ring is always resistant to hydrolysis. Indeed, its hydrolysis is a major metabolic pathway for the thalidomide analogue EM12 (4.198). After administration of EM 12 to marmoset monkeys, two products of hydrolysis, 4.199 and 4.200, were found in urine. The concentrations of the two metabolites were similar after administration of the racemate. In contrast, regioselectivity (i.e.. different ratios of the two metabolites) was seen after separate administration of the enantiomers [125],... 

Hydrazides are formed by the acylation of hydrazines, and have a C-N bond of rather low chemical stability toward hydrolysis. It is, therefore, not surprising that the cleavage of this bond represents a major metabolic pathway for most hydrazides. The reaction is catalyzed by amidases since it can be inhibited by O-ethyl 0-(4-nitrophenyl) phenyl phosphothionate or bis(4-nitrophenyl) phosphate, which are classical inhibitors of this enzyme. 

Caprolactam (5.68, Fig. 5.21) has a seven-membered lactam ring and is a major industrial compound in the production of Nylon , its polymer. This compound shows only moderate levels of toxicity in mice and rats when administered orally. The hydrolysis product 6-aminohexanoic acid (5.69) was a minor metabolite in rats [176]. Hydroxylation in the y-position to yield 5.70 without preliminary hydrolysis of the lactam linkage has been shown to be the major metabolic pathway. This metabolite hydrolyzes in urine to produce 6-amino-4-hydroxyhexanoic acid (5.71), which is in equilibrium with the corresponding lactone (5.72). 

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