Full efficacy with no CNS side-effects: unachievable panacea or reality? DMPK considerations in design of drugs with limited brain penetration

Xenobiotica. 2012 Jan;42(1):11-27. doi: 10.3109/00498254.2011.617847. Epub 2011 Oct 4.


Optimising drug properties can be an important strategy to limit penetration into the CNS and offers advantages in reducing the risk of undesirable neurological effects When considering the design of these drugs it is important to consider the relative influx and efflux rates at the relevant biological membranes The highest degree of restriction at the brain is probably achievable by utilising active transport to exclude compounds from the brain Affinity for the efflux transporters Pgp and BCRP has been achieved in two in-house chemistry programmes by increasing polar surface area, which resulted in highly orally bioavailable low CNS penetrant compounds in preclinical species.

Publication types

  • Review

MeSH terms

  • Blood-Brain Barrier / metabolism
  • Central Nervous System / drug effects*
  • Drug Compounding / methods*
  • Drug Discovery / methods*
  • Drug-Related Side Effects and Adverse Reactions / metabolism*
  • Drug-Related Side Effects and Adverse Reactions / prevention & control
  • Humans
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics
  • Structure-Activity Relationship


  • Pharmaceutical Preparations