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Do drug metabolism and pharmacokinetic departments make any contribution to drug discovery?

Abstract：

:The alignment of drug metabolism and pharmacokinetic departments with drug discovery has not produced a radical improvement in the pharmacokinetic properties of new chemical entities. The reason for this is complex, reflecting in part the difficulty of combining potency, selectivity, water solubility, metabolic stability and membrane permeability into a single molecule. This combination becomes increasingly problematic as the drug targets become more distant from aminergic seven-transmembrane-spanning receptors (7-TMs). The leads available for aminergic 7-TMs, like the natural agonists, are invariably small molecular weight, water soluble and potent. Even moving to 7-TMs for which the agonist is a peptide invariably produces lead matter that is less drug-like (higher molecular weight and lipophilic). The role of drug metabolism departments, therefore, has been to guide chemistry to obtaining adequate, rather than optimal, pharmacokinetic properties for these 'difficult' drug targets. A consistent belief of many researchers is that a high value is placed on optimal, rather than adequate, pharmacokinetic properties. One measure of value is market sales, and when these are examined no clear pattern emerges. Part of the success of amlodipine in the calcium channel antagonist sector must be due to its excellent pharmacokinetic profile, but the best-selling drugs among the angiotensin antagonists and beta-blockers have a much greater market share than other agents with better pharmacokinetic properties. Clearly, many other factors are important in the successful launch of a medicine, some reflected in the manner the compound is developed and the subsequent structure of the labelling. Overall, therefore the presence of drug metabolism in drug discovery has probably contributed most by allowing 'difficult' drug targets to be prosecuted, rather than by guiding medicinal chemists to optimal pharmacokinetics. These 'difficult' target candidates become successful drugs when skilfully developed. There is no doubt that skilful development relies heavily on drug metabolism and pharmacokinetic departments, in this case those with a clinical rather than a preclinical orientation.

journal_name

Clin Pharmacokinet

journal_title

Clinical pharmacokinetics

authors

Smith D,Schmid E,Jones B

doi

10.2165/00003088-200241130-00001

keywords:

subject

Has Abstract

pub_date

2002-01-01 00:00:00

pages

1005-19

issue

eissn

0312-5963

issn

1179-1926

pii

411301

journal_volume

pub_type

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Do drug metabolism and pharmacokinetic departments make any contribution to drug discovery?