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. 2020 Jul 6;25(13):3069.
doi: 10.3390/molecules25133069.

Pharmacokinetics and Metabolism of Liposome-Encapsulated 2,4,6-Trihydroxygeranylacetophenone in Rats Using High-Resolution Orbitrap Liquid Chromatography Mass Spectrometry

Yamen Alkhateeb  1 , Qais Bashir Jarrar  2 , Faridah Abas  3 , Yaya Rukayadi  3 , Chau Ling Tham  4 , Yuen Kah Hay  5 , Khozirah Shaari  1   3
Affiliations

Pharmacokinetics and Metabolism of Liposome-Encapsulated 2,4,6-Trihydroxygeranylacetophenone in Rats Using High-Resolution Orbitrap Liquid Chromatography Mass Spectrometry

Yamen Alkhateeb et al. Molecules. .

Abstract

2,4,6-trihydroxy-3-geranylacetophenone (tHGA) is a bioactive compound that shows excellent anti-inflammatory properties. However, its pharmacokinetics and metabolism have yet to be evaluated. In this study, a sensitive LC-HRMS method was developed and validated to quantify tHGA in rat plasma. The method showed good linearity (0.5-80 ng/mL). The accuracy and precision were within 10%. Pharmacokinetic investigations were performed on three groups of six rats. The first two groups were given oral administrations of unformulated and liposome-encapsulated tHGA, respectively, while the third group received intraperitoneal administration of liposome-encapsulated tHGA. The maximum concentration (Cmax), the time required to reach Cmax (tmax), elimination half-life (t1/2) and area under curve (AUC0-24) values for intraperitoneal administration were 54.6 ng/mL, 1.5 h, 6.7 h, and 193.9 ng/mL·h, respectively. For the oral administration of unformulated and formulated tHGA, Cmax values were 5.4 and 14.5 ng/mL, tmax values were 0.25 h for both, t1/2 values were 6.9 and 6.6 h, and AUC0-24 values were 17.6 and 40.7 ng/mL·h, respectively. The liposomal formulation improved the relative oral bioavailability of tHGA from 9.1% to 21.0% which was a 2.3-fold increment. Further, a total of 12 metabolites were detected and structurally characterized. The metabolites were mainly products of oxidation and glucuronide conjugation.

Keywords: LC-HRMS method validation; liposomes; metabolism; pharmacokinetics; trihydroxygeranylacetophenone.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Base peak chromatograms of plasma, after protein precipitation and extraction, analyzed in negative ion mode; (A) blank plasma and (C) treated plasma, for the 302.5–303.5 mass range revealing no interference with tHGA at RT 7.1 min, (B) blank plasma and (D) treated plasma sample showing for the 204.5–205.5 mass range revealing no interference with the IS at RT at 6.3 min. Treated plasma was obtained from rat blood spiked with 0.5 ng/mL of tHGA.
Figure 2
Figure 2
Plasma tHGA concentrations versus time profile for oral administration of liposomal formulation, oral administration of free tHGA, and intraperitoneal administration of tHGA, at a dose of 20 mg/kg. Data are represented as mean value (n = 6).
Figure 3
Figure 3
Proposed metabolism pathways of tHGA in rats.
Figure 4
Figure 4
The chemical structures of 2,4,6-trihydroxy-3-geranylacetophenone (tHGA) and the internal standard, ibuprofen.
See this image and copyright information in PMC

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