Metabolic responses long-term

In response to this biological data, there has been an active interest in the medicinal chemistry community to develop ACC inhibitors for the treatment of metabolic disorders. This chapter begins by briefly describing notable efforts in the ACC literature prior to 2009. The bulk of the chapter focuses on publications and patents that have appeared in 2009-early 2010. Finally, available data showing the efficacy of ACC inhibition in long-term studies is discussed. 

The effect of any chemical at a biological target depends on its ability to attain a target site concentration that exceeds the threshold required to ehcit the response. The intensity and duration of the response depends on the toxicokinetic properties of the compound (absorption, distribution, metabolism, and excretion) and the nature of the target site interaction (reversible, irreversible). If recovery is complete between successive exposures, no cumulative toxicity is to be expected. However, a short-term acute exposure could potentially add to the long-term burden of a persistent chemical and be relevant for the magnitude of the chronic effect. 

D. Long-term metabolic responses, occurring over the course of hours or days, involve regulation of gene expression to induce changes in levels of one or more enzymes. 

Allopurinol itself is metabolized by xanthine oxidase to form the active metabolite oxypurtnol, which tends to accumulate after chronic administration of the parent drug. This phenomenon contributes to the therapeutic effectiveness of allopurinol in long-term use. Oxypurinol is probably responsible for the antigout effects of allopurinol. Oxypurinol itself is not administered because it is not well absorbed orally. 

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