Metabolic inhibitors

R. M. Hochster andJ. H. Quastel, eds.. Metabolic Inhibitors Comprehensive Treatise, Academic Press, Inc., New York, 1963. 

Regulation of enzyme activity is achieved in a variety of ways, ranging from controls over the amount of enzyme protein produced by the cell to more rapid, reversible interactions of the enzyme with metabolic inhibitors and activators. Chapter 15 is devoted to discussions of enzyme regulation. Because most enzymes are proteins, we can anticipate that the functional attributes of enzymes are due to the remarkable versatility found in protein structures. 

One alternative strategy is to use metabolic inhibitors. Although this approach has not been used with the P-lactams, it is worthwhile bearing in mind as a possibility. It has been used in the production of tetracyclines. 

Amantidine, bromocriptine, mazindol, pergolide, cabergoline, L-dopa/carbidopa, pramipexole, ABT-431, catecholamine metabolism inhibitors (disulfiram, phenelzine, selegiline), amineptine Methylphenidate, /-amphetamine, tropanes, GBR-12909 (partial agonist that may also act as antagonist), modafinil, coca tea... 

Kehrer, J. P Witschi, H. Effects of drug metabolism inhibitors on butylated hydroxyto-luene-induced pulmonary toxicity in mice. Toxicol. Appl. Pharmacol 1980,53,333-342. 

Antimicrobials and Antibiotics Specific metabolic inhibitors, electrophilic organics, cell signaling inhibitors Nonoxidizing Biocides... 

Experimentally, this could be accomplished with the use of permeable metabolic inhibitors, a stereoisomeric form of the drug (Ho et al., 1977), or excess drug concentrations to saturate the enzyme system. 

The uptake process is energy-dependent since it can be inhibited by incubation at a low temperature or by metabolic inhibitors. The energy requirements reflect a coupling of the uptake process with the Na+ gradient across the... 

The enzyme mediating remethylation, 5-methyltetrahy-drofolate-betaine methyltransferase (Fig. 40-4 reaction 4), utilizes methylcobalamin as a cofactor. The kinetics of the reaction favor remethylation. Faulty remethylation can occur secondary to (1) dietary factors, e.g. vitamin B12 deficiency (2) a congenital absence of the apoenzyme (3) a congenital inability to convert folate or B12 to the methylated, metabolically active form (see below) or (4) the presence of a metabolic inhibitor, e.g. an antifolate agent that is used in an antineoplastic regimen. 

FIGURE 52-6 Biosynthesis/metabolism of steroids in the CNS. The conversion of delta5P to dehydroepiandrosterone (DHA) is postulated but not demonstrated. D5P and DHA inhibit and 3oc,5oc-THP potentiates GABAa receptor function, as summarized in Figure 52-7. Solid arrows indicate demonstrated pathways dotted arrows indicate possible pathways. Metabolic inhibitors of enzymes are indicated by . (Redrawn from [12], with permission.)... 

Rees, J.F. and F. Baguet. 1989. Metabolic control of luminescence in the luminous organs of the teleost Porichthys effects of the metabolic inhibitors iodoacetic acid and potassium cyanide. Jour. Exper. Biol. 143 347-357. 

Solomonson, L.P. 1981. Cyanide as a metabolic inhibitor. Pages 11-28 in B. Vennesland, E.E. Conn, C.J. Knowles, J. Westley, and F. Wissing (eds.). Cyanide in Biology. Academic Press, New York. 

Pretreatment with the Type I substrate, ethylmorphine, resulted in 100% mortality in both rats and mice, and aminopyrine pretreatment resulted in 100% and 64% mortality in rats and mice, respectively, exposed to disulfoton (Pawar and Fawade 1978). Nickel chloride, cobalt chloride, or cycloheximide decreased the levels of cytochrome bs, cytochrome c reductase, and total heme in rats (Fawade and Pawar 1983). These electron transport components were further decreased in rats pretreated with these inhibitors and given a single dose of disulfoton. Data from this study suggests an additive effect, since disulfoton also decreases the activities of these components. Evidence of an additive effect between disulfoton and these metabolic inhibitors was suggested by the decrease in ethylmorphine N-demethylase and acetanilide hydroxylase activities when rats were given an inhibitor followed by disulfoton. In another experiment, these inhibitors decreased the activity of delta-aminolevulinic acid synthetase, but this decrease was reversed when disulfoton was administered. 

A number of metabolic inhibitors have been shown to modify the metabolism and disposition of phthalate esters in several aquatic species. 

Although this section deals mainly with the advantages of excised tissues with respect to nasal drug delivery studies, it is important to highlight some important attributes of nasal in situ perfusion model. Although this method does not provide data on systemic absorption, it enables study of the interactions of nasal mucosal enzymes, peptide substrates, and metabolic inhibitors and their implications for nasal drug absorption [13], It also enables the rate of nasal drug absorption to be determined. 

The disposition of insulin was shown to be susceptible to non-absorptive losses to metabolism and mucociliary clearance. Modification of the deposition profile of insulin in the lung showed that higher absorption rates were obtained for more peripheral deposition and co-administration of a metabolic inhibitor reduced losses to exopeptidase metabolism [101], It is acknowledged by the investigators that the IPL technique and the dosing technique of Byron and coworkers are not widely accessible and have therefore not been widely adopted [119], Active absorption has also been studied in this system as described in Sect. 6.2.43. 

Sakagami M, Byron PR, Rypacek F (2002) Biochemical evidence for transcy-totic absorption of polyaspartamide from the rat lung effects of temperature and metabolic inhibitors. J Pharm Sci 91 1958-1968. 

Torchilin VP, et al. TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. Proc Natl Acad Sci USA 2001 98 8786. 

TAT liposomes remain intact within one hour of translocation and slowly migrate through the cell, bypassing the endocytic pathway, to the perinuclear zone where they disintegrate (95). The mechanism utilized by TAT to migrate across the membrane was thought to be energy independent because it operates at similar rates at both 4°C and 37°C (95,96). Cell entry by TAT is also unhindered by metabolic inhibitors such as sodium azide or iodoacetamide (97). Peptides constructed of both the d and l amino acids of Antp can be detected intracellularly, the inference of which is that no specific receptor was required because both isomers had equal potential (98,99). 

There may also be effects via the concentrations of competing cations at the root surface. In studies of short-term uptake of Zn by rice from nutrient solutions containing realistic Zn " " concentrations, Giordano and Mortvedt (1974) found uptake was inhibited by various metabolic inhibitors and by Fe +, Mn +, Ca and Mg + as Cl salts at typical concentrations in flooded soil solutions. Translo-... 

Mechanisms of drug uptake in liver slices were studied in vitro as early as in 1963 by Schanker and Solomon [89]. The results obtained in these experiments are still valuable and show that the influence of temperature, anoxia, metabolic inhibitors and substrate inhibition can be successfully studied in this preparation. However, as mentioned before, at that time the preparation of reproducible precision-cut slices was not feasible. Therefore, the slice incubation technique was virtually abandoned in transport studies after the introduction of the successful isolation of rat hepatocytes. 

Potent metabolic inhibitors of the citric acid cycle. Fluo-roacetate (F-CH2COO ) must first be converted to flu-oroacetyl-S-CoA (by acetyl-CoA synthetase) and thence to fluorocitrate (by citrate synthase) before it can act as a potent metabohc inhibitor of the aconitase reaction as well as citrate transport. Submicromolar concentrations of ( )-erythro-Q iOTOcitTate can irreversibly inhibit citrate uptake by isolated brain mitochondria. 

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