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Clinical Pharmacokinetics

, Volume 41, Issue 13, pp 1005–1019 | Cite as

Do Drug Metabolism and Pharmacokinetic Departments Make Any Contribution to Drug Discovery?

  • Dennis Smith
  • Esther Schmid
  • Barry Jones
Current Opinion

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 β-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.

Keywords

Losartan Drug Metabolism Amlodipine Ritonavir Indinavir 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors would like to thank their many colleagues who have asked the question posed in the title on many occasions.

References

  1. 1.
    Prentis RA, Lis Y, Walker SR. Pharmaceutical innovation by seven UK-owned pharmaceutical companies (1964–1985). Br J Clin Pharmacol 1988; 25: 387–91PubMedCrossRefGoogle Scholar
  2. 2.
    Pinto DJ, Orwat MJ, Wang S, et al. Discovery of l-[3-(aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carbox amide (DPC423), a highly potent, selective, and orally bio-available inhibitor of blood coagulation factor Xa. J Med Chem 2001; 44: 566–78PubMedCrossRefGoogle Scholar
  3. 3.
    Lin JH. Role of pharmacokinetics in the discovery and development of indinavir. Adv Drug Deliv Rev 1999; 39: 33–49PubMedCrossRefGoogle Scholar
  4. 4.
    Chiba M. P450 interaction with HIV protease inhibitors: relationship between metabolic stability, inhibitory potency, and P450 binding spectra. Drug Metab Dispos 2001; 29: 1–3PubMedGoogle Scholar
  5. 5.
    Physician’s desk reference. 55th ed. Montvale (NJ): Medical Economics Company, Inc., 2000: 1202–7Google Scholar
  6. 6.
    Smith DA, Jones B. Variability in drug response as a factor in drug design. Curr Opin Drug Disc Dev 1999; 2: 33–41Google Scholar
  7. 7.
    Van de Waterbeemd H, Smith DA, Jones B. Lipophilicity in PK design: methyl, ethyl, futile. J Comput Aided Mol Des 2001; 15: 273–86PubMedCrossRefGoogle Scholar
  8. 8.
    Israili ZH. Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. J Hum Hypertens 2000; 14 Suppl. 1:S73–86CrossRefGoogle Scholar
  9. 9.
    Belz GG, Butzer R, Kober S, et al. Time course and extent of angiotensin II antagonism after irbesartan, losartan, and valsartan in humans, assessed by angiotensin II dose response and radioligand receptor assay. Clin Pharmacol Ther 1999; 66: 367–73PubMedCrossRefGoogle Scholar
  10. 10.
    Zusman RM. Are there differences among angiotensin receptor blockers? Am J Hypertens 1999; 12: 231S–5SPubMedCrossRefGoogle Scholar
  11. 11.
    Bernhart CA, Perreaut PM, Ferrari BP, et al. A new series of imidazolones: highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists. J Med Chem 1993; 36: 3371–80PubMedCrossRefGoogle Scholar
  12. 12.
    Iwatsubo T, Hirota N, Ooie T, et al. Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol Ther 1997; 73: 147–71PubMedCrossRefGoogle Scholar
  13. 13.
    Davit B, Reynolds K, Yuan R, et al. FDA evaluations using in vitro metabolism to predict and interpret in vivo metabolic drug-drug interactions: impact on labeling. J Clin Pharmacol 1999; 39(9): 899–910PubMedCrossRefGoogle Scholar
  14. 14.
    De Groot MJ, Ackland MJ, Home VA, et al. A novel approach to predicting P450 mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6. J Med Chem 1999; 42: 4062–70PubMedCrossRefGoogle Scholar
  15. 15.
    Afzelius L, Zamora I, Ridderstrom M, et al. Competitive CYP2C9 inhibitors: enzyme inhibition studies, protein homology modeling, and three-dimensional quantitative structure-activity relationship analysis. Mol Pharmacol 2001; 59: 909–19PubMedGoogle Scholar
  16. 16.
    Williams PA, Cosme J, Sridhar V, et al. Mammalian micro-somal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity. Mol Cell 2000; 5: 121–31PubMedCrossRefGoogle Scholar
  17. 17.
    Raag R, Poulos TL. Crystal structures of cytochrome P-450CAM complexed with camphane, thiocamphor, and ad-amantane: factors controlling P-450 substrate hydroxylation. Biochemistry 1991; 30(10): 2674–84PubMedCrossRefGoogle Scholar
  18. 18.
    Gardner IB, Walker DK, Lennard MS, et al. Comparison of the disposition of two novel combined thromboxane synthase inhibitors/thromboxane A2 receptor antagonists in the isolated perfused rat liver. Xenobiotica 1995; 25: 185–97PubMedCrossRefGoogle Scholar
  19. 19.
    Yoshida F, Topliss JG. QSAR model for drug human oral bio-availability. J Med Chem 2000; 43: 2575–85PubMedCrossRefGoogle Scholar
  20. 20.
    Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 23: 3–25CrossRefGoogle Scholar
  21. 21.
    Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 2000; 44(1): 235–49PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Department of Drug MetabolismPfizer Global Research and DevelopmentKentUK

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