Role of drug metabolism in drug discovery and development

Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. High metabolic lability usually leads to poor bioavailability and high clearance. Formation of active or toxic metabolites will have an impact on the pharmacological and toxicological outcomes. There is also potential for drug–drug interactions with coadministered drugs due to inhibition and/or induction of drug metabolism pathways. Hence, optimization of the metabolic liability and drug–drug interaction potential of the new chemical entities are some of the most important steps during the drug discovery process. The rate and site(s) of metabolism of new chemical entities by drug metabolizing enzymes are amenable to modulation by appropriate structural changes. Similarly, the potential for drug–drug interactions can also be minimized by appropriate structural modifications to the drug candidate. However, the optimization of the metabolic stability and drug–drug interaction potential during drug discovery stage has been largely by empirical methods and by trial and error. Recently, a lot of effort has been applied to develop predictive methods to aid the optimization process during drug discovery and development. This article reviews the role of drug metabolism in drug discovery and development. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 5, 397–411, 2001

[1]  J. Vacca,et al.  P450 interaction with HIV protease inhibitors: relationship between metabolic stability, inhibitory potency, and P450 binding spectra. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[2]  P. Watkins,et al.  THE HUMAN CYP3A SUBFAMILY: PRACTICAL CONSIDERATIONS* , 2000, Drug metabolism reviews.

[3]  O. Olesen,et al.  Studies on the Stereoselective Metabolism of Citalopram by Human Liver Microsomes and cDNA-Expressed Cytochrome P450 Enzymes , 1999, Pharmacology.

[4]  K. Griffin,et al.  Molecular mechanisms of cytochrome P-450 induction by xenobiotics: An expanded role for nuclear hormone receptors. , 1999, Molecular pharmacology.

[5]  Shiew-Mei Huang,et al.  FDA Evaluations Using In Vitro Metabolism to Predict and Interpret In Vivo Metabolic Drug‐Drug Interactions: Impact on Labeling , 1999, Journal of clinical pharmacology.

[6]  M. Ingelman-Sundberg,et al.  Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. , 1999, Trends in pharmacological sciences.

[7]  A. Alex,et al.  Novel approach to predicting P450-mediated drug metabolism: development of a combined protein and pharmacophore model for CYP2D6. , 1999, Journal of medicinal chemistry.

[8]  P N Judson,et al.  Knowledge-based expert systems for toxicity and metabolism prediction: DEREK, StAR and METEOR. , 1999, SAR and QSAR in environmental research.

[9]  A. Y. Lu,et al.  Inhibition and Induction of Cytochrome P450 and the Clinical Implications , 1998, Clinical pharmacokinetics.

[10]  A. Hsu,et al.  Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. , 1998, Clinical pharmacokinetics.

[11]  Y. Sugiyama,et al.  Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. , 1998, Pharmacological reviews.

[12]  M. Ackland,et al.  Metabolism of delavirdine, a human immunodeficiency virus type-1 reverse transcriptase inhibitor, by microsomal cytochrome P450 in humans, rats, and other species: probable involvement of CYP2D6 and CYP3A. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[13]  W. Trager,et al.  Oxidation of acetaminophen to its toxic quinone imine and nontoxic catechol metabolites by baculovirus-expressed and purified human cytochromes P450 2E1 and 2A6. , 1998, Chemical research in toxicology.

[14]  D. Shen,et al.  Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. , 1997, The Journal of pharmacology and experimental therapeutics.

[15]  A. Y. Lu,et al.  Role of pharmacokinetics and metabolism in drug discovery and development. , 1997, Pharmacological reviews.

[16]  Barry C. Jones,et al.  Properties of cytochrome P450 isoenzymes and their substrates Part 1: active site characteristics , 1997 .

[17]  F. Beland,et al.  Identification of tamoxifen-DNA adducts formed by 4-hydroxytamoxifen quinone methide. , 1997, Carcinogenesis.

[18]  A. D. Rodrigues,et al.  Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir , 1997, Antimicrobial agents and chemotherapy.

[19]  G. Granneman,et al.  Use of In Vitro and In Vivo Data to Estimate the Likelihood of Metabolic Pharmacokinetic Interactions , 1997, Clinical pharmacokinetics.

[20]  Slobodan Petar Rendic,et al.  Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. , 1997, Drug metabolism reviews.

[21]  M. Pirmohamed,et al.  Relevance of induction of human drug-metabolizing enzymes: pharmacological and toxicological implications. , 2003, British journal of clinical pharmacology.

[22]  D. Walker,et al.  Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics , 1996, Medicinal research reviews.

[23]  A. D. Rodrigues,et al.  Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. , 1996, The Journal of pharmacology and experimental therapeutics.

[24]  J. Caldwell.  The Role of Drug Metabolism in Drug Discovery and Development , 1996 .

[25]  P. Neuvonen,et al.  Rifampin drastically reduces plasma concentrations and effects of oral midazolam , 1996, Clinical pharmacology and therapeutics.

[26]  E. Gallagher,et al.  Role of cytochrome P4501A2 in chemical carcinogenesis: implications for human variability in expression and enzyme activity. , 1995, Pharmacogenetics.

[27]  P. Chakravarty,et al.  Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[28]  H. Yamazaki,et al.  Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. , 1994, The Journal of pharmacology and experimental therapeutics.

[29]  K. Korzekwa,et al.  Activation of CYP3A4: evidence for the simultaneous binding of two substrates in a cytochrome P450 active site. , 1994, Biochemistry.

[30]  J. Miners,et al.  In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylase. , 1994, British journal of clinical pharmacology.

[31]  W. Trager,et al.  Bioactivation and irreversible binding of the cognition activator tacrine using human and rat liver microsomal preparations. Species difference. , 1993, Drug metabolism and disposition: the biological fate of chemicals.

[32]  M. J. Coon,et al.  The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. , 1993, DNA and cell biology.

[33]  F. Guengerich.  Metabolic activation of carcinogens. , 1992, Pharmacology & therapeutics.

[34]  S. Wrighton,et al.  The human hepatic cytochromes P450 involved in drug metabolism. , 1992, Critical reviews in toxicology.

[35]  F. Guengerich.  Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. , 1990, Chemical research in toxicology.

[36]  C. Westerlund,et al.  Quantitative relationships between structure and microsomal oxidation rate of 1,4-dihydropyridines. , 1986, Chemico-biological interactions.

[37]  L. Pershing,et al.  Cytochrome P-450 metabolic-intermediate complex formation and induction by macrolide antibiotics; a new class of agents. , 1982, Xenobiotica; the fate of foreign compounds in biological systems.

[38]  J. Mccall,et al.  Sulfation of minoxidil by liver sulfotransferase. , 1982, Biochemical pharmacology.

[39]  S. Sligar,et al.  Substrate interaction with cytochrome P-450. , 1981, Pharmacology & therapeutics.