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. 2018 Feb;391(2):185-196.
doi: 10.1007/s00210-017-1448-2. Epub 2017 Dec 12.

Pharmacokinetic study of tianeptine and its active metabolite MC5 in rats following different routes of administration using a novel liquid chromatography tandem mass spectrometry analytical method

Małgorzata Szafarz  1 , Agnieszka Wencel  2 , Krzysztof Pociecha  2 , Filip A Fedak  2 , Piotr Wlaź  3 , Elżbieta Wyska  2
Affiliations

Pharmacokinetic study of tianeptine and its active metabolite MC5 in rats following different routes of administration using a novel liquid chromatography tandem mass spectrometry analytical method

Małgorzata Szafarz et al. Naunyn Schmiedebergs Arch Pharmacol. 2018 Feb.

Abstract

Tianeptine is an atypical antidepressant with a unique mechanism of action and recently it has been also reported that its major metabolite, compound MC5, possesses pharmacological activity similar to that of the parent drug. The current study aims to investigate the pharmacokinetics (PK) of both tianeptine and MC5 after intravenous or intraperitoneal administration of the parent drug as well as the metabolic ratio of MC5 in rats. To achieve these goals an LC-MS/MS method using the small sample volume for the quantitation of tianeptine and its active metabolite MC5 in rat plasma and liver perfusate has been developed and validated. Following an intravenous administration of tianeptine pharmacokinetic parameters were calculated by non-compartmental analysis. The average tianeptine volume of distribution at steady state was 2.03 L/kg and the systemic clearance equaled 1.84 L/h/kg. The mean elimination half-lives of tianeptine and MC5 metabolite were 1.16 and 7.53 h, respectively. The hepatic clearance of tianeptine determined in the isolated rat liver perfusion studies was similar to the perfusate flow rate despite the low metabolic ratio of MC5. Mass spectrometric analysis of rat bile indicated that tianeptine and MC5 metabolite are eliminated with bile as glucuronide and glutamine conjugates. Bioavailability of tianeptine after its intraperitoneal administration was 69%. The PK model with a metabolite compartment developed in this study for both tianeptine and MC5 metabolite after two routes of administration may facilitate tianeptine dosage selection for the prospective pharmacological experiments.

Keywords: MC5 metabolite; Mass spectrometry; Pharmacokinetics; Rats; Tianeptine.

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Conflict of interest statement

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All of the animal experiments described in this paper were approved by the Institutional Animal Care and Ethics Committee of the Jagiellonian University (nr 226/2015).

Figures

Fig. 1
Fig. 1
Metabolic pathways for tianeptine
Fig. 2
Fig. 2
Product ion mass spectra of [M + H+]+ ions of tianeptine (a), metabolite MC5 (b), and IS (c) with the proposed fragmentation paths
Fig. 3
Fig. 3
Representative chromatogram of QC sample at the LLOQ concentration (1 ng/mL). a Tianeptine. b Metabolite MC5. c Internal standard. d Blank sample
Fig. 4
Fig. 4
Pharmacokinetic model of tianeptine and its metabolite MC5 after two routes of administration of the parent drug. (F is fraction absorbed, V c, V m, and V t are volumes of the central, metabolite, and tissue compartments, respectively, k 12 and k 21 are first order distribution and redistribution rate constants, k e and k eM are the first order rate constants for elimination of the parent drug and metabolite, respectively, and f m is the fraction of the dose metabolized
Fig. 5
Fig. 5
Measured (symbols) and pharmacokinetic model predicted (lines) concentration versus time profiles of tianeptine and its metabolite MC5 following intravenous (a) and intraperitoneal (b) administration of the parent drug to rats at the doses of 1 and 10 mg/kg, respectively
Fig. 6
Fig. 6
The perfusate concentration-time profile of tianeptine in the isolated perfused rat liver (mean ± SD; n = 3) after a single dose administration of the drug (300 μg)
Fig. 7
Fig. 7
Mass spectra of rat bile sample scanned in the PI (precursor ion) 292 mode. M/z 437.7 — tianeptine; M1—metabolite MC3; M2—metabolite MC5; M3 and M4—conjugates of tianeptine with glutamine and glucuronic acid, respectively; M5 and M6—conjugates of metabolite MC5 with glutamine and glucuronic acid, respectively
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