Skip to main content
Journal cover image

Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry.

Publication ,  Journal Article
Wang, P-F; Neiner, A; Kharasch, ED
Published in: Drug Metab Dispos
October 2019

Efavirenz (more specifically the S-enantiomer) is a cornerstone antiretroviral therapy for treatment of HIV infection. The major primary metabolite is S-8-hydroxyefavirenz, which does not have antiretroviral activity but is neurotoxic. Cytochrome P450 2B6 (CYP2B6) is the major enzyme catalyzing S-8-hydroxyefavirenz formation. CYP2B6 genetics and drug interactions are major determinants of clinical efavirenz disposition and dose adjustment. In addition, as a prototypic CYP2B6 substrate, S-efavirenz and analogs can inform on the structure, activity, catalytic mechanisms, and stereoselectivity of CYP2B6. Metabolism of R-efavirenz by CYP2B6 remains unexplored. This investigation assessed S-efavirenz metabolism by clinically relevant CYP2B6 genetic variants. This investigation also evaluated R-efavirenz hydroxylation by wild-type CYP2B6.1 and CYP2B6 variants. S-Efavirenz 8-hydroxylation by wild-type CYP2B6.1 and variants exhibited positive cooperativity and apparent cooperative substrate inhibition. On the basis of Clmax values, relative activities for S-efavirenz 8-hydroxylation were in the order CYP2B6.4 > CYP2B6.1 ≈ CYP2B6.5 ≈ CYP2B6.17 > CYP2B6.6 ≈ CYP2B6.7 ≈ CYP2B6.9 ≈ CYP2B6.19 ≈ CYP2B6.26; CYP2B6.16 and CYP2B6.18 showed minimal activity. Rates of R-efavirenz metabolism were approximately 1/10 those of S-efavirenz for wild-type CYP2B6.1 and variants. On the basis of Clmax values, there was 14-fold enantioselectivity (S > R-efavirenz) for wild-type CYP2B6.1, and 5- to 22-fold differences for other CYP2B6 variants. These results show that both CYP2B6 516G > T (CYP2B6*6 and CYP2B6*9) and 983T > C (CYP2B6*16 and CYP2B6*18) polymorphisms cause canonical diminishment or loss-of-function variants for S-efavirenz 8-hydroxylation, provide a mechanistic basis for known clinical pharmacogenetic differences in efavirenz disposition, and may predict additional clinically important variant alleles. Efavirenz is the most stereoselective CYP2B6 drug substrate yet identified and may be a useful probe for the CYP2B6 active site and catalytic mechanisms. SIGNIFICANCE STATEMENT: Clinical disposition of the antiretroviral S-efavirenz is affected by CYP2B6 polymorphisms. Expressed CYP2B6 with 516G>T (CYP2B6*6 and CYP2B6*9), and 983T>C (CYP2B6*16 and CYP2B6*18) polymorphisms had a diminishment or loss of function for efavirenz 8-hydroxylation. This provides a mechanistic basis for efavirenz clinical pharmacogenetics and may predict additional clinically important variant alleles. Efavirenz metabolism showed both cooperativity and cooperative substrate inhibition. With greater than 10-fold enantioselectivity (S- vs. R- metabolism), efavirenz is the most stereoselective CYP2B6 drug substrate yet identified. These findings may provide mechanistic insights.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Drug Metab Dispos

DOI

EISSN

1521-009X

Publication Date

October 2019

Volume

47

Issue

10

Start / End Page

1195 / 1205

Location

United States

Related Subject Headings

  • Stereoisomerism
  • Reverse Transcriptase Inhibitors
  • Recombinant Proteins
  • Polymorphism, Single Nucleotide
  • Pharmacology & Pharmacy
  • Insecta
  • Humans
  • HIV Infections
  • Cytochrome P-450 CYP2B6
  • Cyclopropanes
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wang, P.-F., Neiner, A., & Kharasch, E. D. (2019). Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry. Drug Metab Dispos, 47(10), 1195–1205. https://doi.org/10.1124/dmd.119.086348
Wang, Pan-Fen, Alicia Neiner, and Evan D. Kharasch. “Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry.Drug Metab Dispos 47, no. 10 (October 2019): 1195–1205. https://doi.org/10.1124/dmd.119.086348.
Wang P-F, Neiner A, Kharasch ED. Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry. Drug Metab Dispos. 2019 Oct;47(10):1195–205.
Wang, Pan-Fen, et al. “Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry.Drug Metab Dispos, vol. 47, no. 10, Oct. 2019, pp. 1195–205. Pubmed, doi:10.1124/dmd.119.086348.
Wang P-F, Neiner A, Kharasch ED. Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry. Drug Metab Dispos. 2019 Oct;47(10):1195–1205.
Journal cover image

Published In

Drug Metab Dispos

DOI

EISSN

1521-009X

Publication Date

October 2019

Volume

47

Issue

10

Start / End Page

1195 / 1205

Location

United States

Related Subject Headings

  • Stereoisomerism
  • Reverse Transcriptase Inhibitors
  • Recombinant Proteins
  • Polymorphism, Single Nucleotide
  • Pharmacology & Pharmacy
  • Insecta
  • Humans
  • HIV Infections
  • Cytochrome P-450 CYP2B6
  • Cyclopropanes