Drug candidates biotransformation

Jemal M. et al., 1999. A versatile system of high-flow high performance hquid chromatography with tadem mass spectrometry for rapid direct-injection analysis of plasma samples for quantitation of a /1-lactam drug candidate and its open-ring biotransformation product. Rapid Commun Mass Spectrom 13 1462. 

Femandez-Metzler, C. L., Owens, K. G., Baillie, T. A., and King, R. C. (1999). Rapid liquid chromatography with tandem mass spectrometry-based screening procedures for studies on the biotransformation of drug candidates. Drug Metab. Dispos. 27 32-40. 

Chemical inhibition, which involves an evaluation of the effects of known CYP enzyme inhibitors on the metabolism of a drug candidate by human liver microsomes. Chemical inhibitors of CYP must be used cautiously because most of them can inhibit more than one CYP enzyme and some chemicals can inhibit one enzyme but activate another. Some chemical inhibitors are mechanism-based inhibitors that require biotransformation to a metabolite that inhibits or inactivates CYP. 

The lipophilicity of the drug candidate is informative because drag candidates with a log D7 4 greater than 1 are likely to require biotransformation to more polar metabolites to facilitate their elimination in urine or bile. The chemical structure of the drug candidate provides important information on the potential for enzymes other than CYP to be involved in its metabolism. Table 9 shows a variety... 

Another yeast, Rhodotorula rubra MY 2169, has been shown to reduce a ketosulfone 8 to the corresponding tram-hydroxysulfone 9 (Scheme 19.8). This hydroxysulfone is an intermediate in the drug candidate L-685,393 (10), a carbonic anhydrase inhibitor.81 Results of this biotransformation yielded gram quantities of product with a de of >96%. Studies by Zeneca discuss additional screening experiments aimed at finding microorganisms to reduce a similar ketosulfone.82... 

The implicit objective of the chapter is to warn medicinal chemists against the danger of over-simplihcation. For too many drug discoverers, biotransformation begins and ends with CYP-catalyzed oxidations. As a result of this narrow view, little is done computationally and experimentally before the development phases to obtain a comprehensive view of the biotransformation of lead and preclinical candidates. One can only wonder about the proportion of metabolism-related side-effects that could have been avoided during clinical phases had medicinal chemists been more attentive to potential toxihcation reactions and drug-drug interactions caused by non-CYP reactions. 

Fernandez-Metzler, C.L. Owens, K.G. Baillie, T.A. King, R.C. Rapid Liquid Chromatography with Tandem Mass Spectrometry-based Screening Procedures for Studies on the Biotransformation of Drug Candidates, Drug Metab. Dispos. 27, 32-40 (1999). 

Jemal, M. Ouyang, Z. Xia, Y.-Q. Powell, M.L. A Versatile System of High-Flow High Performance Liquid Chromatography with Tandem Mass Spectrometry for Rapid Direct-Injection Analysis of Plasma Samples for Quantitation of a p -Lactam Drug Candidate and its Open Ring Biotransformation Product, Rapid Commun. Mass Spectrom. 13(14), 1462-1471 (1999). 

The results from these studies provide information on whether a drug may inhibit the biotransformation of another drug when the two are coadministered. LC-MS approaches continue to be used routinely to identify and select drug candidates that have a lower potential for drug-drug interactions. 

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