Drug Metabolism

The development of new and novel techniques and technologies such as combinatorial chemistry, high throughput screening, molecular and cell biology, medical imaging and decoding or sequencing of the human genomes in pharmaceutical research has given discovery scientists the ability to deliver large numbers of new chemical entities (NCE).. However, the success rate of NCEs entering the market place is unacceptably low with estimate of 1 in 5000 compounds. The major reasons for failure of NCEs are poor clinical efficacy, serious undesired side effects, adverse drug reactions and unfavorable drug metabolism and pharmacokinetics (DMPK). Therefore, it has been recognized that in addition of good pharmacological activity (potency and selectivity), safety and pharmacokinetics are crucial determinants of the ultimate clinical success of a drug candidate. The early refinement of these properties has been regarded as essential features of the drug candidate selection process and it has compelled the pharmaceutical industry to integrate more greatly DMPK functions into the early stages of drug discovery. Such DMPK integration should allow the selection of a drug candidate that has good oral absorption and bioavailability, optimum half-life, favorable clearance, and acceptable metabolic and toxicological profiles in patients. Drug optimization of pharmacokinetic parameters depends on a good understanding of the factors that affect the ADME processes and will help to guide drug design efforts. By seeking a balance based upon the rule of three (exposure-activity-toxicity), drug metabolism scientists have opened up a new front in the effort to develop safer and more efficacious drugs.