Application to Futile Deacetylation Reactions

It has been shown by using NMR spectroscopy in conjunction with isotopelabelling studies that there is a significant degree of deacetylation followed by reacetylation (futile deacetylation) of paracetamol metabolites in vivo in the rat [58]. If this also occurs in humans, then it may help to explain the observed incidence of nephrotoxicity of paracetamol in that the process would result in levels of the potent nephrotoxin 4-aminophenol in vivo. Confirmation of the levels of futile deacetylation in individual metabolites of isotopically labelled paracetamol in man has been achieved by using directly coupled HPLC-NMR 

A final example of the use of this strategy to examine futile deacetylation comes from work on the beta-blocking drug practolol where a radio-labelled 13C/14C drug was dosed to rats and the urine profiled by HPLC with UV, radioactivity, NMR and MS-MS detection [61]. As shown by the structure below, practolol can be considered to be an analogue of paracetamol with a beta-blocker side-chain  

The amount of futile acetylation observed for this compound in the rat, at ca. 7-10% for parent compound and metabolites, was less than that seen for phenacetin and similar to that found for paracetamol itself. The bulk of the radio-label was rapidly excreted in urine as practolol itself (albeit with 7-10% reacetylation) and the remainder as either the ring-hydroxylated metabolite or its glucuronide conjugate. As in previous examples, deuterated methanol was used in the mobile phase rather than methanol in order to be able to more easily observe the acetyl resonances of practolol and related compounds. 

---