Ketamine as a Probe for Medetomidine Stereoisomer Inhibition of Human Liver Microsomal Drug Metabolism

Kharasch, Evan D.; Herrmann, S.; Labroo, Rita

doi:10.1097/00000542-199212000-00023

Cited by 32 publications

(30 citation statements)

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“…, 2001), the use of dexmedetomidine (Dexdomitor ® , Orion Pharma, Espoo, Finland) would be expected to further decrease the risk for CYP2B11 inhibition in vivo vs. medetomidine. Dexmedetomidine was even measured to be a weaker inhibitor than medetomidine in agreement with findings in human liver microsomes where levomedetomidine was slightly more potent than dexmedetomidine (Kharasch et al. , 1992).…”

Section: Resultssupporting

confidence: 87%

“…The structurally similar reversal agent atipamezole often used to antagonize the effects of medetomidine also inhibited CYP2B11 much more than the other canine rP450s. This was not unexpected as submicromolar IC 50 s for medetomidine were reported previously in human liver microsomes (Kharasch et al. , 1992), but the use of rP450s definitively identified the P450 isoform inhibited in dogs.…”

Section: Resultssupporting

confidence: 81%

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Canine CYP2B11 metabolizes and is inhibited by anesthetic agents often co-administered in dogs

Baratta

Zaya

White

et al. 2010

Journal of Veterinary Pharmacology and Therapeutics

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Medetomidine is a well-established sedative and analgesic for dogs and cats. As a premedicant for anesthesia regimens that also include other agents, medetomidine can also provide a dose-sparing effect. While there are likely several reasons for the dose-sparing effect of medetomidine, the role of metabolic drug-drug interactions at the single enzyme level has not yet been examined. Using a panel of individually expressed canine cytochromes P450 cloned from beagle liver, this report demonstrates that medetomidine is an extremely potent CYP2B11 inhibitor (IC(50) < 10 nm) and that ketamine and midazolam are CYP2B11 substrates with high intrinsic clearances. These in vitro findings suggest that under some circumstances, medetomidine (i.e. 'perpetrator') may inhibit the metabolic clearance of some high metabolic clearance drugs (i.e. 'victims') with which it is commonly co-administered via the CYP2B11 pathway. However, as the dose-sparing effect of medetomidine premedication commonly results in anesthetic dose reduction, any increased plasma concentrations of victim drugs caused by medetomidine would still be lower than if no dose reduction had been made. Further studies are needed to characterize whether medetomidine possesses the potential to cause pharmacokinetic interactions. In conclusion, the ability of recombinant P450s to define canine-specific drug clearance pathways and P450 inhibitors should prove useful in identifying drug combinations that may require dose adjustments in dogs.

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Section: Resultssupporting

confidence: 87%

Section: Resultssupporting

confidence: 81%

Canine CYP2B11 metabolizes and is inhibited by anesthetic agents often co-administered in dogs

Baratta

Zaya

White

et al. 2010

Journal of Veterinary Pharmacology and Therapeutics

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“…In the rabbit, ketamine showed extensive extrahepatic clearance. Medetomidine is known to reduce significantly the hepatic microsomal metabolism of ketamine in human liver samples in vitro (Kharasch et al. 1992).…”

Section: Discussionmentioning

confidence: 99%

Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus)

Gerritsmann

Stalder

Seilern-Moy

et al. 2012

Veterinary Anaesthesia and Analgesia

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“…This situation is common in the treatment of CRPS patients as a retrospective chart review of the 16 CRPS patients studied in our initial pharmacokinetic/pharmacodynamic study of (R,S)-Ket (Goldberg et al , 2011a) indicated that these patients received 73 different concomitant medications at different dosages along with their (R,S)-Ket infusion; i.e., an average of 9.4 medications per individual (Supplemental Data, Table S3). Metabolic drug interactions involving (R,S)-Ket and (S)-Ket have previously been reported involving medetomidine (Kharasch et al ., 1992), dexmedeomidine (Nama et al ., 2010) and rifampicin (Noppers et al ., 2011) and Ket itself has been shown to induce CYPs in rats (Chan et al ., 2005; Chen and Chen, 2010). As the use of (R,S)-Ket increases in the management of postoperative and perioperative pain and in opioid tolerant patients (Loftus et al ., 2010; Angst and Clark, 2010) and in emergency room treatments (Lester et al ., 2010) it is likely that the reported interactions will also increase.…”

Section: Discussionmentioning

confidence: 86%

Stereoselective and regiospecific hydroxylation of ketamine and norketamine

Desta¹,

Moaddel²,

Ogburn³

et al. 2012

Xenobiotica

136

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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 HLMs and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site Michaelis-Menten, 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.

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Ketamine as a Probe for Medetomidine Stereoisomer Inhibition of Human Liver Microsomal Drug Metabolism

Cited by 32 publications

References 0 publications

Canine CYP2B11 metabolizes and is inhibited by anesthetic agents often co-administered in dogs

Canine CYP2B11 metabolizes and is inhibited by anesthetic agents often co-administered in dogs

Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus)

Stereoselective and regiospecific hydroxylation of ketamine and norketamine

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