Stereoselective and regiospecific hydroxylation of ketamine and norketamine

Zeruesenay Desta, Ruin Moaddel, Evan T. Ogburn, Cong Xu, Anuradha Ramamoorthy, Swarajya Lakshmi Vattem Venkata, Mitesh Sanghvi, Michael E. Goldberg, Marc C. Torjman, Irving W. Wainer

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine [(R,S)-Ket] to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine [(R,S)-norKet] to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f). The enantiomers of Ket and norKet were incubated with characterized human liver microsomes (HLMs) and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site MichaelisMenten, Hill or substrate inhibition equation. 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates. 5a and 4b were detected in plasma samples from patients receiving (R,S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response.

Original languageEnglish
Pages (from-to)1076-1087
Number of pages12
JournalXenobiotica
Volume42
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Cytochrome P-450 CYP3A
Hydroxylation
Ketamine
Cytochromes
Metabolites
Pharmacogenetics
Liver Microsomes
Enzymes
Drug Interactions
Drug interactions
Enantiomers
Liver
Plasmas
Kinetics
Substrates
norketamine
Cytochrome P-450 CYP2B6
Therapeutics

Keywords

  • Complex regional pain syndrome
  • Cytochrome
  • Dehydronorketamine
  • Depression
  • Hydroxyketamine
  • Hydroxynorketamine
  • Ketamine
  • P450s

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology
  • Biochemistry
  • Health, Toxicology and Mutagenesis

Cite this

Desta, Z., Moaddel, R., Ogburn, E. T., Xu, C., Ramamoorthy, A., Venkata, S. L. V., ... Wainer, I. W. (2012). Stereoselective and regiospecific hydroxylation of ketamine and norketamine. Xenobiotica, 42(11), 1076-1087. https://doi.org/10.3109/00498254.2012.685777

Stereoselective and regiospecific hydroxylation of ketamine and norketamine. / Desta, Zeruesenay; Moaddel, Ruin; Ogburn, Evan T.; Xu, Cong; Ramamoorthy, Anuradha; Venkata, Swarajya Lakshmi Vattem; Sanghvi, Mitesh; Goldberg, Michael E.; Torjman, Marc C.; Wainer, Irving W.

In: Xenobiotica, Vol. 42, No. 11, 11.2012, p. 1076-1087.

Research output: Contribution to journalArticle

Desta, Z, Moaddel, R, Ogburn, ET, Xu, C, Ramamoorthy, A, Venkata, SLV, Sanghvi, M, Goldberg, ME, Torjman, MC & Wainer, IW 2012, 'Stereoselective and regiospecific hydroxylation of ketamine and norketamine', Xenobiotica, vol. 42, no. 11, pp. 1076-1087. https://doi.org/10.3109/00498254.2012.685777
Desta Z, Moaddel R, Ogburn ET, Xu C, Ramamoorthy A, Venkata SLV et al. Stereoselective and regiospecific hydroxylation of ketamine and norketamine. Xenobiotica. 2012 Nov;42(11):1076-1087. https://doi.org/10.3109/00498254.2012.685777
Desta, Zeruesenay ; Moaddel, Ruin ; Ogburn, Evan T. ; Xu, Cong ; Ramamoorthy, Anuradha ; Venkata, Swarajya Lakshmi Vattem ; Sanghvi, Mitesh ; Goldberg, Michael E. ; Torjman, Marc C. ; Wainer, Irving W. / Stereoselective and regiospecific hydroxylation of ketamine and norketamine. In: Xenobiotica. 2012 ; Vol. 42, No. 11. pp. 1076-1087.
@article{a91680fcf1034ad4be842f8c6bac7d95,
title = "Stereoselective and regiospecific hydroxylation of ketamine and norketamine",
abstract = "The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine [(R,S)-Ket] to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine [(R,S)-norKet] to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f). The enantiomers of Ket and norKet were incubated with characterized human liver microsomes (HLMs) and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site MichaelisMenten, Hill or substrate inhibition equation. 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates. 5a and 4b were detected in plasma samples from patients receiving (R,S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response.",
keywords = "Complex regional pain syndrome, Cytochrome, Dehydronorketamine, Depression, Hydroxyketamine, Hydroxynorketamine, Ketamine, P450s",
author = "Zeruesenay Desta and Ruin Moaddel and Ogburn, {Evan T.} and Cong Xu and Anuradha Ramamoorthy and Venkata, {Swarajya Lakshmi Vattem} and Mitesh Sanghvi and Goldberg, {Michael E.} and Torjman, {Marc C.} and Wainer, {Irving W.}",
year = "2012",
month = "11",
doi = "10.3109/00498254.2012.685777",
language = "English",
volume = "42",
pages = "1076--1087",
journal = "Xenobiotica",
issn = "0049-8254",
publisher = "Informa Healthcare",
number = "11",

}

TY - JOUR

T1 - Stereoselective and regiospecific hydroxylation of ketamine and norketamine

AU - Desta, Zeruesenay

AU - Moaddel, Ruin

AU - Ogburn, Evan T.

AU - Xu, Cong

AU - Ramamoorthy, Anuradha

AU - Venkata, Swarajya Lakshmi Vattem

AU - Sanghvi, Mitesh

AU - Goldberg, Michael E.

AU - Torjman, Marc C.

AU - Wainer, Irving W.

PY - 2012/11

Y1 - 2012/11

N2 - The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine [(R,S)-Ket] to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine [(R,S)-norKet] to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f). The enantiomers of Ket and norKet were incubated with characterized human liver microsomes (HLMs) and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site MichaelisMenten, Hill or substrate inhibition equation. 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates. 5a and 4b were detected in plasma samples from patients receiving (R,S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response.

AB - The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine [(R,S)-Ket] to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine [(R,S)-norKet] to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f). The enantiomers of Ket and norKet were incubated with characterized human liver microsomes (HLMs) and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site MichaelisMenten, Hill or substrate inhibition equation. 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates. 5a and 4b were detected in plasma samples from patients receiving (R,S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response.

KW - Complex regional pain syndrome

KW - Cytochrome

KW - Dehydronorketamine

KW - Depression

KW - Hydroxyketamine

KW - Hydroxynorketamine

KW - Ketamine

KW - P450s

UR - http://www.scopus.com/inward/record.url?scp=84867184164&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867184164&partnerID=8YFLogxK

U2 - 10.3109/00498254.2012.685777

DO - 10.3109/00498254.2012.685777

M3 - Article

VL - 42

SP - 1076

EP - 1087

JO - Xenobiotica

JF - Xenobiotica

SN - 0049-8254

IS - 11

ER -