Metabolic clearance, drug design

A number of different approaches, have been designed to characterize the metabolic clearance of compounds, namely antibody inhibition, correlation analysis, chemical inhibitors and cDNA-expressed CYPs. As expected the science underlying these tools has developed over the past two decades reducing the need to use several approaches simultaneously to make unequivocal conclusions regarding the CYP isoform responsible for the metabolism of a drug of interest. For the purposes of the current chapter, only the latter two are discussed. The readers are referred to recent reviews that describe in detail the science behind antibody inhibition and correlation analysis [87-89]. 

In the case of remifentanil it was also proved that, as predicted by the basic principles used in soft drug design, the possibility of drug interactions could be minimized by building metabolic considerations into the structure. Clearance, volume of distribution, and terminal half-life data indicated that coadministration of esmolol has no significant (P < 0.05) effect on the pharmacokinetics (or pharmacodynamics) of remifentanil in rats, despite both drugs being metabolized by nonspecific esterases (99,100). 

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