title: Regioselective biotransformation of CNS drugs and its clinical impact on adverse drug reactions.
abstract: BACKGROUND
  Adverse drug reactions (ADRs) continue to be one of the major causes of failure in drug development while limiting the clinical utilities of many drugs. Contribution of the metabolites formed in vivo to ADRs could be more significant than we might have expected.
  
  
  METHODS
  This review focuses on the relationship between regioselectivity in biotransformation and the ADRs of drugs acting on the central nervous system (CNS). "Regioselectivity" is defined as an exclusively or significantly preferential metabolic reaction at one (or several) site(s) on the substrate molecule. Several CNS drugs and toxicants, of which the metabolites play pivotal roles in ADRs, are summarized in details with the highlight on the roles of metabolism in both toxification and detoxification. The article also discusses in silico predictions of regioselectivity and the formation of toxic metabolites which are becoming increasingly important.
  
  
  CONCLUSIONS
  Researchers working on CNS drugs face particular challenges in predicting drug metabolism and potential toxicities of their metabolites. A number of factors contribute to the difficulty of accurate prediction of metabolite disposition in the human brain. Better knowledge of regioselectivity in biotransformation and elucidation of the relationships between biotransformations and ADRs would definitely help designing new compounds with lower bioactivation potentials and rejuvenating the older drugs whose clinical applications are restricted by their ADRs. Administrating drugs by alternative routes such as the intranasal, transdermal, sublingual, and buccal routes could also be a strategy to reduce unwanted metabolite formations.
authors.affiliation: The Chinese University of Hong Kong, School of Pharmacy, Faculty of Medicine, Shatin, New Territories, Hong Kong SAR.
authors.forename: Yin Cheong
authors.initials: YC
authors.lastname: Wong
authors.forename: Shuai
authors.initials: S
authors.lastname: Qian
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001711:Biotransformation; D002491:Central Nervous System Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D015262:Xenobiotics
chemical_list: D000927:Anticonvulsants; D014150:Antipsychotic Agents; D002491:Central Nervous System Agents; D015262:Xenobiotics