Drug metabolism poor metabolizers

The drug discovery and development processes are time consuming and costly endeavors. It has been reported that on average it takes 10 to 15 years and costs more than 800 million to bring a molecule from discovery to market.12 Compounds fail for various reasons. One that accounts for a reported 40% of failures in clinical trials is poor pharmacokinetics.3 In an effort to improve the number of compounds that exhibit optimal absorption, distribution, metabolism, elimination (ADME), and pharmacokinetic (PK) properties and reach development, drug metabolism and pharmacokinetic scientists continually implement new technologies and compound screening approaches. 

Oxidative drug metabolism is extremely complex and possibly the most poorly understood ADME property. Rapid metabolism is unacceptable for drug candidates, except for drugs whose metabolite is the active moiety, because it causes duration of action to be too short. Considerable work has focused on the liver enzyme CYP3A4, which is responsible for the metabolic clearance of approximately 50% of marketed drugs. Recent approaches used to model and understand drug metabolism include database matching, quantum mechanics, QSAR, and structure-based analyses. 

Intestinal Metabolism Intestinal drug metabolism can occur by microflora present in the gut lumen, as well as by enzymes present in luminal fluids and in the intestinal mucosa [166], Metabolism of xenobiotics by gut microflora is low in comparison to metabolism by the gut mucosa and liver [62], However, the intestinal microflora (e.g., Bacteroides and Bifidobacteria) may play an important role in the first-pass metabolism of compounds that are poorly or incompletely absorbed by the gut mucosa, especially in the lower parts of the intestine. This bacterial metabolism is largely degradative,... 

Prodrugs provide a vehicle by which the bioavailablUity of a drug displaying poor water solubility can be enhanced or a method of targeting diseased areas of the body. Following uptake, the drug is frequently released by the action of metabolic enzymes. For example, the human enzyme believed to be primarily responsible for the rapid in vivo hydrolysis of valaciclovir to aciclovir has recently been isolated and characterized (Scheme 1.18). ... 

D. Aminoglycosides do not penetrate most cells, and most drug-metabolizing enzymes are found on the inside of the cells. Therefore, aminoglycosides are poorly metabolized, and nearly all of an intravenous dose can be recovered in the urine. 

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