Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics.
Drug metabolism input to the discovery process had historically been on an empirical case-by-case basis, since, detailed descriptors of the effect on pharmacokinetics of a change in structure or physicochemical property were not available. Considerable advances have been made in recent years, such that basic rules can be applied to predict the behavior of a compound in man based on physicochemistry and structure. This is particularly true in the areas of absorption, distribution, and clearance. In particular, knowledge of the reactions catalyzed by the enzymes of drug metabolism, including the cytochrome P450 super family, can be used in the design of new chemical entities, together with the usual pharmacological-derived SAR. The combination of both pharmacokinetics and pharmacodynamics at the discovery stage leads to drugs with optimum performance characteristics. Such drugs are easier to develop, representing a huge saving in resources. Moreover, the marketed compound is much more likely to find high clinical utilization. This review uses dofetilide, fluconazole, and amlodipine to highlight the multifaceted consequences of changing chemical structure, in terms of drug disposition, and reinforces these principles with examples from the literature.
Smith
D A
DA
Department of Drug Metabolism, Pfizer Central Research, Sandwich, Kent, U.K.
Jones
B C
BC
Walker
D K
DK
D000042:Absorption; D017311:Amlodipine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000935:Antifungal Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D015725:Fluconazole / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D010600:Pharmacology; D010627:Phenethylamines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D000935:Antifungal Agents; D000959:Antihypertensive Agents; D004364:Pharmaceutical Preparations; D010627:Phenethylamines; D013449:Sulfonamides; D017311:Amlodipine; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; C063533:dofetilide