Metabolic instability

Severe 4 Infection in a patient with systemic toxicity or metabolic instability (e.g., fever, chills, tachycardia, hypotension, confusion, vomiting, leukocytosis, acidosis, severe hyperglycemia, or azotemia). 

Several examples have already been pointed out in which the properties of the solute itself can impact on the results obtained from a transport experiment. Metabolic instability and propensity for nonspecific adsorption are problems which can frequently be encountered and must be considered any time a new solute is to be studied. In addition to these problems, there are several other solute-related factors which must be considered in the design and interpretation of transport studies. 

DPP-8/9 selectivity, it exhibited poor oral bioavailability in the rat due to metabolic instability of the piperazine ring. 

The first reported selective inhibitors of the HATs p300 and PCAF were peptides representing structurally simple bi-substrate analogs of H3 and acetyl-CoA [10, 11]. Hence, p300 was inhibited by Lys-CoA 1 and the more specific PCAF by the 20-amino-acid peptide H3-CoA-20 2 (Figure 11.2). Unfortunately, these inhibitors showed low cell permeability and high metabolic instability, which decreases their suitability for investigations in vivo [12]. 

The potential utility of peptides as therapeutic agents with clinical applications is limited as a consequence of intrinsic peptide properties such as metabolic instability or poor transmembrane mobility. Hence, the design and synthesis of meta-bolically stable peptide analogs that can either mimic or block the bioactivity of natural peptides or enzymes is an important area of medicinal chemistry research. Numerous structural modifications to peptides have been examined in pursuit of molecules with more desirable properties [1-3]. These modified structures, peptidomimetics, are nonpeptide molecules that imitate the desired properties of the natural substances. 

In 1986, just prior to its release, seizures were reported in a small number of nondepressed, bulimic patients taking bupropion. Bupropion was removed from the market by the manufacturer until it was determined that seizures in this vulnerable population appeared to be related to high doses (>450 mg) of bupropion used in the context of metabolic instability. The drug was finally released in the United States in 1989. 

However, the binding affinities of 197,206 and 207 [0.3%, 0.1% and <0.01%, respectively, relative to oestradiol (100%)] for the oestrogen specific acceptor protein of the rat uterus suggest that a steric or an electronic effect, rather than metabolic instability, is responsible for the absence of oestrogenic activity in these compounds. But a clear answer cannot be given because biological data of the direct 6,6-dimethyl-6-carba-analogues are not known so far. 

Naked plasmid DNA was not only trapped in the cytoplasm around the site of microinjection, as visualized by fluorescence in situ hybridization (FISH) or using FITC-labeled DNA, but was also eliminated rapidly at physiological temperature (Lechardeur et al., 1999). The disposal of the DNA was completely prevented when the cells were kept at 4°C (Lechardeur et al., 1999). A similar conclusion was reached by monitoring the amount of microinjected expression cassette by the polymerase chain reaction (PCR) (Pollard et al., 2001), suggesting that the metabolic instability of naked DNA contributes to the low efficiency of gene transfer (Lechardeur et al., 1999 Mirzayans et al, 1992 Neves etal., 1999 Pollard et al., 2001). 

While isolation of a specific inhibitor will be necessary to assess the definitive role of the cytosolic nuclease in the low transfection efficiency in vivo, circumstantial evidence suggests that the metabolic instability of plasmid DNA represents one of the cellular barriers to gene transfer. Microinjection of DNA complexes with PEI has augmented the transfection efficiency (Pollard et al., 1998). Although the stability of the PEI-complexed DNA has not been determined in vivo, it has been demonstrated that the nuclease resistance of plasmid DNA is dramatically increased upon complex formation in vitro (Cappaccioli et al., 1993 Chiou et al., 1994 Thierry et al., 1997). Therefore, it is conceivable that faster diffusional mobility and decreased nuclease susceptibility jointly lead to the enhanced nuclear targeting efficiency of the PEI-condensed plasmid DNA. 

Mechanisms of nuclear transport, 229 Membrane permeabilization, 343 Metabolic genes, 22 Metabolic instability, 216 Metallothionein, 22 Microenvironment, 443 Molossin, 350... 

Yin H, Tran P, Greenberg GE, et al. Methanol solvent may cause increased apparent metabolic instability in in vitro assays. Drug Metab Dispos 2001 29 185-193. 

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