Development of HPLC-MS/MS Method for Simultaneous Detection of Esketamine and Norketamine: Application to Pharmacokinetics Drug Interactions Affected by Dexmedetomidine.
Abstract
<h4>Purpose</h4>Dexmedetomidine (DEX) and esketamine (ESK) are often used together during anesthesia. This study aimed to establish a sensitive and reliable HPLC-MS/MS method for simultaneous quantification of ESK and its active metabolite norketamine (NORK) in beagle dog plasma and to investigate the pharmacokinetic drug-drug interactions (DDIs) between DEX and ESK/NORK.<h4>Methods</h4>A simple protein precipitation method using acetonitrile was applied for plasma sample preparation. After chromatographic separation, analytes were detected by HPLC-MS/MS in positive ion mode using multiple reaction monitoring (MRM). The mass transitions were m/z 238.10→125.10 for ESK, m/z 224.10→125.10 for NORK, and m/z 354.20→209.00 for the internal standard (proadifen). Six beagle dogs were intramuscularly administered 1 mg/kg ESK alone in the first period (ESK group). After a washout, the same dogs received intravenous DEX (2 µg/kg) for 7 consecutive days, followed by co-administration of ESK (DEX+ESK group). The pharmacokinetic parameters of ESK and NORK were calculated using DAS software. Independent-sample <i>t</i> test was used to compare the differences of pharmacokinetic parameters between ESK group and DEX+ESK group, and P < 0.05 indicated a statistically significant difference.<h4>Results</h4>Both ESK and NORK exhibited good linearity within the concentration range of 1-400 ng/mL, and the methodological validation met the requirements. When ESK was used in combination with DEX, the main pharmacokinetic parameters of ESK and NORK changed, the C<sub>max</sub>, AUC<sub>(0-24)</sub> and AUC<sub>(0-∞)</sub> of ESK increased, the C<sub>max</sub>, of NORK decreased, and the AUC<sub>(0-12)</sub> and AUC<sub>(0-∞)</sub> of NORK increased too.<h4>Conclusion</h4>A novel HPLC-MS/MS method was developed and validated and successfully applied to simultaneously quantify ESK and NORK in beagle dog plasma. The pharmacokinetic DDI results indicate that DEX could inhibit the metabolism of ESK, alter pharmacokinetic characteristics of ESK and its metabolite NORK, and significantly increase the systemic exposure of both ESK and NORK.
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