Direct inhibition acid transporter

The ability of doxombicin formulated with the copolymer to avoid accumulation in acidic cytoplasmic vesicles is probably the most important contributor to its mechanism of action. Resistance-modulating agents and some polymer conjugates can partially reduce the dmg resistance mediated by ATP-dependent transporters by either directly inhibiting these transporters , or by switehing the dmg transport from passive diffusion to endocytosis. At the same time, they cannot overcome the endosomal barrier that represents the seeond level of resistance in drug resistant cells. The fact that Pluronic L61/doxombicin can effectively penetrate the plasma membrane of resistant cells and, at the same time, avoid sequestration in the vesicles suggests that this product may be more clinically effective than other doxombicin-based products. 

I. values ranged between 1 and 20 mM. The compounds did not act as uncouplers or directly inhibit ATP synthesis. However, naringenln, some of the flavones, and the clnnamates acids inhibited th hydrolysis of ATP catalyzed by mitochondrial Mg -ATPase. The Inhibition of substrate oxidation appears to result from alterations and perturbations induced in the inner membrane as evidenced by Interference with carrier-mediated transport processes. 

Methotrexate is a folic acid analogue. Its mechanism of action is based on the inhibition of dihydrofolate reductase. Inhibition of dihydrofolate reductase leads to depletion of the tetrahydrofolate cofactors that are required for the synthesis of purines and thymidylate (see Fig. 2). Enzymes that are required for purine and thymidylate synthesis are also directly inhibited by the polyglutamates of methotrexate which accumulate with dihydrofolate reductase inhibition. The mechanisms that can cause resistance include decreased transport of methotrexate into the tumor cells, a decreased affinity of the antifolate for dihydrofolate reductase, increased concentrations of intracellular dihydrofolate reductase and decreased thymidylate synthetase activity. 

Mechanism of Action. Atovaquone appears to selectively inhibit electron transport in susceptible microorganisms.6 This inhibition directly decreases production of ATP in the microorganism and may interfere with nucleic acid synthesis, ultimately resulting in death of the parasite. 

Thiazides and the related diuretics inhibit the transport of sodium in the early distal tubules, which results in the enhanced elimination of sodium, chloride, and water. Potassium and sodium bicarbonate elimination is also enhanced calcium excretion is decreased, uric acid is retained. Glomerular filtration rate is decreased. The antihypertensive effects may be the result of direct arteriolar dilation but the full mechanism has not been identified. 

Primary herbicidal effects are followed by secondary ones that show up before death of the plant cell. The 70-S ribosomes of wheat chloroplasts are decreased by bleaching pyridazinones in the light, but not in the dark ( 9) A prominent mode of action is observed upon the composition of fatty acids by, e.g., BAS 13338 (SAN 9785) (24, 5), which does not substcuatially interfere with carotenoid biosynthesis. Good direct inhibition of photosynthetic electron transport (I50 3 x 10 7m) is observed with the phenylpyridazinone BAS 100822 electron transport inhibition of other phenyl-pyridazinones is less than with BAS 100822 (28). 

The yeast cell membrane may be envisioned as a selectively permeable barrier that serves a vital role in the organism s ability to maintain osmotic balance and regulate transport of essential nutrients into and metabolites (including ethanol) out of the cell. Ethanol is soluble in both aqueous and lipid phases of the cell membrane and its formation and passive effusion eventually interferes with structure and function of the membrane. Particularly important in this regard are the cell-membrane-associated transport enzymes such as those responsible for uptake of sugars and critical amino acids. During active fermentation at warm temperatures, ethanol accumulates intracellularly faster than it can be eliminated from the cell. This situation worsens as extracellular concentrations increase. Thus, temperature- and ethanol-directed inhibition is likely the result of the time delay arising from passive diffusion coupled with impaired membrane function. 

The suggestion that there may be a sodium-dependent ascorbic acid transport mechanism in the pigmented layer of the ciliary epithelium (the layer which faces the blood side) fits well with a study conducted by Chu and Candia (1988), who isolated the rabbit iris-ciliary body and measured trans-tissue fluxes of labeled ascorbic acid. A net flux of ascorbic acid was observed in what would have been the blood-to-aqueous humor direction. Importantly, this net flux could be inhibited by phloridzin added to the blood side but not when added to the aqueous side. This finding is consistent with a model where active ascorbic acid is accumulated by the pigmented cells on the blood side of the ciliary epithelium bilayer, then passes via gap junctions into the nonpigmented cells, and finally diffuses into the aqueous humor. However, the situation may be more complex since cultured cells derived from the nonpigmented ciliary epithelium have also been shown to be capable of sodium-dependent ascorbic acid accumulation (Delamere et al., 1993). 

---