Metabolic lability

The pharmacokinetic profile of (16) and its two analogues were investigated in Sprague-Dawley rats. Removal of the metabolically labile tert-butyl group on the aryl moiety slowed metabolism and the rate of clearance. However, the overall half-life of (17a) was unaffected because of a lower volume of distribution. On the other hand, (17b) showed an increased half-life (ca. 3h versus 1 h) compared to (16) and (17a). While the oral bioavailability of (16) was negligible, (17a) and (17b) were better absorbed, with bioavailability values of 39% and 17%, respectively. While undoubtedly improved in terms of pharmacokinetics compared to (16), the bioactivity of (17a) and (17b) awaits validation in vivo. 

It is obvious that when a molecule is metabolically labile, it will not be sufficiently available atthe site of action . The problem maybe addressed when the labile site(s) ina molecule is(are) known, because metabolic transformation may be reduced, if not blocked, by appropriate modification of the chemical structure. The same applies in the field of crop protection science. If an insecticide is metabolically labile and transformed by plant CYPs, it will not be available for protection against the targeted insects. 

Unnatural amino acids are added to the growth medium in most experiments. There are a large number of amino acid and amine transporters that are relatively nonspecific and which may help to transport the unnatural amino acids into cells. From measurements of cytoplasmic levels of amino acids, it is found that a large number of unnatural amino acids are efficiently transported to the E. coli cytoplasm in millimolar concentrations. Highly charged or hydrophilic amino acids may require derivatization (e.g., esterification, acylation) with groups that are hydrolyzed in the cytoplasm. Metabolically labile amino acids or analogues (e.g., a-hydroxy acids, A-methyl amino acids) may require strains in which specific metabolic enzymes are deleted. 

The predominant interaction of CYP3A4 is via hydrophobic forces and the overall lowering of lipophilicity can reduce metabolic lability to the enzyme. Figure 7.14 shows the relationship between unboimd intrinsic clearance in man and lipophilicity for a variety of CYP3A4 substrates. The substrates are cleared by a variety of metabolic routes including N-dealkylation, aromatization and aromatic and aliphatic hydroxylation. The trend for lower metabolic lability with lower lipophilicity is maintained regardless of structure or metabolic route. 

In the case of remifentanil tv o sites of hydrolysis were incorporated into the molecule to provide sufficient metabolic lability [12, 13]. 

Oxadiazoles have often attracted the attention of medicinal chemists as stable bioiso-steres of metabolically labile esters. 1,3,4-Oxadiazoles are generally prepared by cyclodehydration of 1,2-diacylhydrazines or their equivalents. Symmetrical 2,5-disubstituted examples were able to be rapidly prepared in a one-pot condensation-cyclodehydration of benzoic acids (2 equiv) with hydrazine dihydrochloride, in the presence of... 

In this case, unlike prednisolone a metabolically labile ester function occupies the 17j0-position. The ester is hydrolyzed to an inactive carboxylic acid, A -cortienic acid etabonate and then into the lead compound A cortienic acid in the biological system. 

Figure 5.9. Stractures and metabolically labile bonds of of lidocaine, tocaiitide, and mexiletine.

As described previously, the presystemic metabolism of drugs may occur via various mechanisms. It is obvious, therefore, that coadministration of a low bioavailable drug and its metabolism inhibitor, which can selectively inhibit any of the contributing processes, would result in increased fractional absorption and hence a higher bioavailability. In fact, this approach seems to be a promising alternative to overcome the enzymatic barriers to oral delivery of metabolically labile drugs such as peptides and proteins. 

Often these types of experiments can point to the portion of the drug that has been metabolically altered, rather than completely identify the structure of the metabolite itself However, as mentioned previously, this is often enough in the discovery phase to alert the structural chemists to the metabolically labile portion of the molecule, but sometimes further experiments... 

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