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Pharmacokinetics and Disposition of Prolonged-Release Ketamine Tablets for Treatment of Neuro-Psychiatric Diseases

  • Introduction: Ketamine (KET) is widely used as anaesthetic drug. Beside its pronounced an-aesthetic effects as caused by antagonism of NMDA receptors, ketamine also causes potent analgesia. Moreover, There are ample new evidences, firstly, that 2R,6R/2S,6S-enantiomers of hydroxynorketamine (HNK), exert neuro-modulating effects by AMPA-receptor activation and, secondly, that the plasma levels of norketamine (n-KET) after oral dosing are higher than after intravenous administration. From the physicochemical point of view ketamine is expected to be a substrate of drug transporters. Thus, it was the aim of this study to separate and quantify KET and its metabolites in human serum, urine and feces; investigate the role of transporter proteins in the intestinal absorption, distribution and elimination of ketamine; and evaluate pharmacokinetics and metabolism of a newly developed prolonged-release keta-mine dosage form to confirm its suitability for chronic treatment of CNS-diseases (e.g. de-pression) according to the new “ketamine metabolite paradigm”. Materials and methods: Quantification of ketamine was done by a LC-MS/MS-based quantifi-cation method on the QTRAP4000 instrument. Samples were extracted by methyl tert-butyl ether after addition of sodium carbonate to liberate the free base; Single transfected MDCKII cells overexpressing OCT1, OCT2, OCT3, and MATE1 or MATE2K, and HEK293 cells over-expressing OATP2B1 were used to study the cellular uptake of ketamine. Inside-out lipovesi-cles were used to determine the affinity of ketamine to the efflux transporter P-glycoprotein (P-gp). Uptake into cells or vesicles was determined by liquid scintillation counting. Func-tionality of all in vitro systems was assured by using in each case appropriate probe sub-strates; The dose-escalation study was performed in five consecutive periods (7 days wash-out) in 15 healthy subjects (5 females and 10 males. 20-35 years, BMI 19.4-27.6 kg/m2). Results: We introduce for the first time the separation and quantification of the active me-tabolites 2R,6R/2S,6S-HNK; Ketamine was shown to be taken up significantly in a time- and concentration-dependent manner by OCT1-3. The affinity to OCT transporters at pH=6.5 was several fold higher than that at pH=7.4. ), ketamine showed a significant but low affinity to P-gp. In contrast to this, we could not detect any transport of ketamine by MATE1 / 2K or OACPT2B1; and PR-KET was safe and well tolerated with higher metabolites productivity, different pharmacokinetic properties and longer T1/2 when compared to IV-KET or IR-KET. Conclusion: the uptake transporters OCT1 & 3 and the efflux transporter P-gp may play a role in the intestinal absorption of the drug. On the other side, P-gp, MATE1 / 2K and OCT are not expected to contribute significantly to tissue (brain) distribution or renal excretion of ketamine; Moreover, the prolonged-release ketamine undergoes dose-dependent “first-pass” metabolism which generates substantially increased plasma exposure of downstream me-tabolites with potential neuro-modulating effects compared to ketamine after intravenous administration.
  • Ketamin (KET) ist als Anästhetikum weit verbreitet. Neben seinen ausgeprägten ästhetischen Wirkungen, die durch den Antagonismus der NMDA-Rezeptoren verursacht werden, bewirkt Ketamin auch eine starke Analgesie. Darüber hinaus gibt es neue Beweise, erstens, dass 2R, 6R / 2S, 6S-Enantiomere von Hydroxynorketamin (HNK), neuromodulierende Effekte durch AMPA-Rezeptor-Aktivierung und zweitens, dass die Plasmaspiegel von Norketamin (n-KET) nach oraler Dosierung höher sind als nach intravenöser Verabreichung. Aus physikalisch-chemischer Sicht wird erwartet, dass Ketamin ein Substrat von Arzneimitteltransporter ist. Daher ist es das Ziel dieser Studie, KET und seine Metaboliten in menschlichem Serum, Urin und Kot zu trennen und zu quantifizieren. Die Rolle von Transporterproteinen bei der intestinalen Absorption, die Verteilung und Eliminierung von Ketamin und ZNS-Erkrankungen (z.B. Depressionen) nach dem neuen "Ketamin-Metabolit-Paradigma" werden untersucht.

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Author: Mahmoud Hasan
Title Additional (English):Pharmacokinetics and Disposition of Prolonged-Release Ketamine Tablets for Treatment of Neuro-Psychiatric Diseases
Title Additional (German):Pharmakokinetik und Disposition von Ketamintabletten mit verlängerter Freisetzung zur Behandlung von neuropsychiatrischen Krankheiten
Advisor:Prof. Dr. Martin Fromm, Prof. Dr. Werner Siegmund
Document Type:Doctoral Thesis
Date of Publication (online):2017/11/16
Granting Institution:Ernst-Moritz-Arndt-Universität, Mathematisch-Naturwissenschaftliche Fakultät (bis 31.05.2018)
Date of final exam:2017/10/17
Release Date:2017/11/16
Tag:dehydronorketamine, ketamine, prolonged release tablet
GND Keyword:Depression, Ketamin, hydroxynorketamine
Faculties:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Pharmazie
DDC class:500 Naturwissenschaften und Mathematik / 540 Chemie