Clin Pharmacokinet. 2002;41(13):1005-19. doi: 10.2165/00003088-200241130-00001.
Do drug metabolism and pharmacokinetic departments make any contribution to drug discovery?.
Clinical pharmacokinetics
Dennis Smith, Esther Schmid, Barry Jones
Affiliations
Affiliations
- Department of Drug Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom. [email protected]
PMID: 12403640
DOI: 10.2165/00003088-200241130-00001
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.
References
- J Clin Pharmacol. 1999 Sep;39(9):899-910 - PubMed
- J Hum Hypertens. 2000 Apr;14 Suppl 1:S73-86 - PubMed
- Drug Metab Dispos. 2001 Jan;29(1):1-3 - PubMed
- Xenobiotica. 1995 Feb;25(2):185-97 - PubMed
- J Med Chem. 1993 Oct 29;36(22):3371-80 - PubMed
- Adv Drug Deliv Rev. 1999 Oct 18;39(1-3):33-49 - PubMed
- J Med Chem. 2000 Jun 29;43(13):2575-85 - PubMed
- Mol Cell. 2000 Jan;5(1):121-31 - PubMed
- J Med Chem. 2001 Feb 15;44(4):566-78 - PubMed
- Am J Hypertens. 1999 Dec;12(12 Pt 3):231S-235S - PubMed
- Clin Pharmacol Ther. 1999 Oct;66(4):367-73 - PubMed
- Pharmacol Ther. 1997;73(2):147-71 - PubMed
- Curr Opin Drug Discov Devel. 1999 Jan;2(1):33-41 - PubMed
- J Med Chem. 1999 Oct 7;42(20):4062-70 - PubMed
- Br J Clin Pharmacol. 1988 Mar;25(3):387-96 - PubMed
- Biochemistry. 1991 Mar 12;30(10):2674-84 - PubMed
- Mol Pharmacol. 2001 Apr;59(4):909-19 - PubMed
- Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26 - PubMed
- J Comput Aided Mol Des. 2001 Mar;15(3):273-86 - PubMed
- J Pharmacol Toxicol Methods. 2000 Jul-Aug;44(1):235-49 - PubMed
Substances
MeSH terms
Publication Types