Localised hydrolysis

This assumption is akin to the hypothesis of localised hydrolysis invoked by Robinson and Harned to explain the reversal of the order of activity coefficients of alkali metal hydroxides, fluorides, acetates and formates in water. 

The rate-determining step in the absorption of dmg esters such as fluphenazine decanoate (which has an aqueous solubility of about 1 part per million) is the hydrolysis of the dmg at the surface of the oil droplet. Hydrolysis of the fluphenazine decanoate to its soluble alcohol therefore depends on the state of dispersion and surface area of the droplets. Dispersing the droplets by mbbing the site of injection or by violent exercise can result in excessive dosage, with toxic effects. Exercise also causes increased blood flow and, as absorption is a dynamic process requiring the sweeping away of the dmg from the localised absorption site, this increased flow increases the rate of dmg dispersal. 

The theoretical basis for such a rationale has been laid in the recent work of Pack et al [161,162]. Using the Poisson-Boltzmann approximation the pH-contour maps on and near the surface of B-DNA ( poly(dG).poly(dC)) have been constructed under simulated conditions of 45 mM tris buffer with 3mM Mg at pH 7.5. Three domains of high ET concentration (>10p.M) are predicted one is spread over the minor groove and two are localised in the major groove near N7(G) and C5(C) for a G.C base pair [114,163]. The reduction in pH by two units would translate into one hundred fold increase in TC production compared to the bulk rate. This is manifested in the accelerated rate of DNA-mediated hydrolysis. Elaborating on the two state model of Islam et al [149] in which the DE is either free or statically bound. Pack and Wong [163(a)] concluded that the catalysis by DNA is primarily an electrostatic effect of acidic domains in the surface grooves of the nucleic acid. While such computations were found satisfactory for a //-BaPDE hydrolysis, they could not adequately reproduce... 

When vesicles are polymerised, the interaction between substrate and vesicle is modified. We therefore expect different reactivities for monomer vesicles and their polymerised counterparts. This hypothesis has been borne out experimentally with regard to hydrolysis and aminolysis of nitrophenylesters. Polymerisation allows better control of reactivity by localising the substrate at different vesicular sites. 

Histone deacetylases (HDACs, EC number 3.5.1) remove acetyl groups from A -acetyl lysines by hydrolysis, both on histones and non-histone proteins, hence are more generally referred to as lysine deacetylases (KDACs). HDACs are grouped into four classes based on sequence homology and mechanism (Table 5.2). The first two classes, sometimes referred to as classical HDACs, are zinc-dependent and their activity is inhibited by hydroxamic acids, e.g. trichostatin A (TSA). The third class, referred to as Sirtuins, are NAD -dependent proteins and are not inhibited by TSA. The fourth class is also zinc-dependent, but is considered an atypical category based on low sequence homology to classes I and II. Class I and IV HDACs are mainly found in the nucleus and are expressed in many cell types, while the expression of class II HDACs, which are able to shuttle in and out of the nucleus, is tissue specific. Sirtuin localisation depends on the particular isoform (cytoplasm, mitochondria and nucleus). 

Owing to the high viscosities and the need for careful control of the relative amounts of organic acid and caustic soda, achieving good mixing is difficult but of great importance. Localised pockets of un-neutralised acid can result in acid hydrolysis of the product. 

---