Metabolism drug, microbial studies

Briand, J., Blehaut, H., Calvayrac, R., Laval-Martin, D. Use of a microbial model for the determination of drug effects on cell metabolism and energetics study of citrulline-malate. Biopharm. Drug Dispos. 1992,13 1-22. 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

In the 1970s, Smith and Rosazza introduced the concept of microbial models of mammalian metabolism [38,39]. Two reviews in this area were published in 1999 [40,41]. Since these, there have been numerous reports describing the use of microbial biotransformation in drug metabolism studies [42-54]. These reports demonstrated that microbial enzymes were able to... 

In Table 2 antibiotic and steroid biotransformations are only poorly represented compared to their actual frequency more than 50 examples of antibiotic transformations were already reported in 1975 [9, 38, 39] a hsting of steroid microbial transformations, published in 1981, covers 853 substrates [40], while more than 1000 examples have been hsted for the 1979-1992 period [41-44]. However, most of the examples reported in those areas have been essentially oriented towards the preparation of new active compounds rather than towards a study of detoxification metabohtes derived from drugs. Alkaloids represent another group of biologically active natural substances where microbial metabolism was explored relatively early and exhaustively [40,45-47]. 

The use of microorganisms as a complementary tool in the study of drug metabolism is certainly becoming more popular. The examples cited above provide additional evidence of the utility of such systems as alternative in vitro models for investigating drug metabolism in humans. However, as mentioned above, no in vitro model could ever completely replace animal experimentation in medical research, and the predictive value of microbial systems, even if they frequently correlate with their animal counterpart, is questionable. Nevertheless, microorganisms can be used as a reliable and efficient alternative to small animals or... 

Metabolism studies are essential for approval of any clinically useful drug. Microorganisms have been successfully used as in vitro models for prediction of mammalian drug metabolism due to the significant similarity of certain microbial enzyme systems, specifically fungi, with mammalian liver enzyme systems.66 The following metabolism study represents the first for a cembranoid diterpene and may aid future development of other cembranoids as clinically useful drugs. 

The use of microbial systems as in vitro models for drug metabolism in humans has been proposed, as there are many similarities between certain microbial enzyme systems and mammalian liver enzyme systems. The major advantages of using microorganisms are their ability to produce significant quantities of metabolites that would otherwise be difficult to obtain from animal systems or by chemical synthesis, and the considerable reduction in operating costs compared with animal studies. 

This is an example of the direct interdependence of drug development on basic biomedical research. Knowledge gained from studies on microbial metabolism and knowledge of organic chemistry were used to develop an effective therapeutic agent. Nevertheless, chance also played a role in the sense that the activity of isoniazid was discovered and not overlooked. However, the sequence of discoveries did not stop here. 

Microbial systems show distinct advantages in certain areas which make them attractive to drug metabolism studies [13, 14, 26] ... 

Information gained from microbial metabolism studies can be used as an early indication of the likely metabolic routes of a particular drug in mammalian systems. 

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