DRUG METABOLISM IN THE BRAIN AND HOW IT CAN ALTER DRUG RESPONSE

J Pharm Pharmacogn Res 2(Suppl. 1): S40, 2014

Special supplement with the abstract book of LATINFARMA 2013

Plenary Lecture

PL 006: DRUG METABOLISM IN THE BRAIN AND HOW IT CAN ALTER DRUG RESPONSE

Tyndale R.

Toronto, Canada.
Abstract

The brain has a unique expression profile of drug and toxin metabolizing cytochrome P450 enzymes (CYPs); multiple forms of CYPs have been identified in the brains of different species including rodents, dogs, monkeys and humans. These CYPs are genetically polymorphic, similar to their expression in the liver meaning some people have high levels, while other people have no expression. These CYPs are uniquely expressed and regulated in a cell and brain-region specific manner and can metabolize many centrally relevant compounds including centrally acting drugs, neurotoxins and neurotransmitters. Drugs and toxins that act on the central nervous system (CNS) may be metabolized in situ in the brain, and differences in in situ metabolism may contribute to variation in an individual’s response to drugs and toxins. Studies in artificial in vitro systems, with added cofactors, indicate that brain CYPs have similar substrate specificity and in vitro kinetics to their hepatic forms. We have shown that brain CYPs are metabolically active in situ using a radio-labeled suicide inhibitor, which takes advantage of the brain CYP metabolic activity of the animal, injected directly into the brain of a living rat. We have also subsequently demonstrated in vivo, using a similar brain inhibitor or induction approach, that enzymes within the brain can alter drug effect. This is illustrated using CYP2B inactivation of the anesthetic propofol within the rat brain and its resulting impact on sedation, CYP2B activation of a neurotoxic pesticide chlorpyrifos and its alteration of neurotoxicity. Likewise we have shown that brain CYP2D activation of codeine to morphine is important to the early time points for analgesia, and that brain CYP2D may importantly alter risk for Parkinson’s disease through its ability to inactivate neurotoxins such as MPTP. These results indicate that brain CYPs are actively able to metabolize CNS acting drugs and neurotoxins and can contribute significantly to local drug response. The induction of brain CYPs by nicotine and alcohol, and higher levels in the brains of smokers and alcoholics, suggests that in addition to pharmacogenetic variation, commonly used drugs could also alter responses to centrallyacting drugs and toxins. More broadly these studies indicate that brain CYPs are active in situ and have sufficient local enzymatic activity to meaningfully alter the pharmacology of centrally acting drugs and neurotoxins.