Drug metabolism in human brain: High levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite

Varsha Agarwal, Reddy P. Kommaddi, Khader Valli, Daniel Ryder, Thomas Hyde, Joel Kleinman, Henry W. Strobel, Vijayalakshmi Ravindranath

Research output: Contribution to journalArticle

Abstract

Cytochrome P450 (P450) is a super-family of drug metabolizing enzymes. P450 enzymes have dual function; they can metaboize drugs to pharmacologically inactive metabolites facilitating their excretion or biotransform them to pharmacologically active metabolites which may have longer half-life than the parent drug. The variable pharmacological response to psychoactive drugs typically seen in population groups is often not accountable by considering dissimilarities in hepatic metabolism. Metabolism in brain specific nuclei may play a role in pharmacological modulation of drugs acting on the CNS and help explain some of the diverse response to these drugs seen in patient population. P450 enzymes are also present in brain where drug metabolism can take place and modify therapeutic action of drugs at the site of action. We have earlier demonstrated an intrinsic difference in the biotransformation of alprazolam (ALP) in brain and liver, relatively more α-hydroxy alprazolam (α-OHALP) is formed in brain as compared to liver. In the present study we show that recombinant CYP3A43 metabolizes ALP to both α-OHALP and 4-hydroxy alprazolam (4-OHALP) while CYP3A4 metabolizes ALP predominantly to its inactive metabolite, 4-OHALP. The expression of CYP3A43 mRNA in human brain samples correlates with formation of relatively higher levels of α-OH ALP indicating that individuals who express higher levels of CYP3A43 in the brain would generate larger amounts of α-OHALP. Further, the expression of CYP3A43 was relatively higher in brain as compared to liver across different ethnic populations. Since CYP3A enzymes play a prominent role in the metabolism of drugs, the higher expression of CYP3A43 would generate metabolite profile of drugs differently in human brain and thus impact the pharmacodynamics of psychoactive drugs at the site of action.

Original languageEnglish (US)
Article numbere2337
JournalPLoS One
Volume3
Issue number6
DOIs
StatePublished - Jun 11 2008
Externally publishedYes

Fingerprint

Alprazolam
Anti-Anxiety Agents
Cytochromes
anxiety
cytochromes
Metabolites
Metabolism
pharmacokinetics
Brain
metabolites
brain
drugs
metabolism
Pharmaceutical Preparations
Liver
Cytochrome P-450 Enzyme System
liver
Cytochrome P-450 CYP3A
enzymes
Psychotropic Drugs

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Drug metabolism in human brain : High levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite. / Agarwal, Varsha; Kommaddi, Reddy P.; Valli, Khader; Ryder, Daniel; Hyde, Thomas; Kleinman, Joel; Strobel, Henry W.; Ravindranath, Vijayalakshmi.

In: PLoS One, Vol. 3, No. 6, e2337, 11.06.2008.

Research output: Contribution to journalArticle

Agarwal, Varsha ; Kommaddi, Reddy P. ; Valli, Khader ; Ryder, Daniel ; Hyde, Thomas ; Kleinman, Joel ; Strobel, Henry W. ; Ravindranath, Vijayalakshmi. / Drug metabolism in human brain : High levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite. In: PLoS One. 2008 ; Vol. 3, No. 6.
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