Korean J Physiol Pharmacol.  2017 Jan;21(1):45-54. 10.4196/kjpp.2017.21.1.45.

Metabolism and excretion of novel pulmonary-targeting docetaxel liposome in rabbits

• Wang J
• Zhang L
• Wang L
• Liu Z
• Yu Y

• KMID: 2371067
• DOI: http://doi.org/10.4196/kjpp.2017.21.1.45

Abstract

Our study aims to determine the metabolism and excretion of novel pulmonary-targeting docetaxel liposome (DTX-LP) using the in vitro and in vivo animal experimental models. The metabolism and excretion of DTX-LP and intravenous DTX (DTX-IN) in New Zealand rabbits were determined with ultraperformance liquid chromatography tandem mass spectrometry. We found DTX-LP and DTX-IN were similarly degraded in vitro by liver homogenates and microsomes, but not metabolized by lung homogenates. Ultra-performance liquid chromatography tandem mass spectrometry identified two shared DTX metabolites. The unconfirmed metabolite M(un) differed structurally from all DTX metabolites identified to date. DTX-LP likewise had a similar in vivo metabolism to DTX-IN. Conversely, DTX-LP showed significantly diminished excretion in rabbit feces or urine, approximately halving the cumulative excretion rates compared to DTX-IN. Liposomal delivery of DTX did not alter the in vitro or in vivo drug metabolism. Delayed excretion of pulmonary-targeting DTX-LP may greatly enhance the therapeutic efficacy and reduce the systemic toxicity in the chemotherapy of non-small cell lung cancer. The identification of M(un) may further suggest an alternative species-specific metabolic pathway.

Keyword

Animal model; Chemotherapy; Cumulative excretion rate; Liquid chromatography; Lung cancer; Mass spectrometry

MeSH Terms

Animal Experimentation
Carcinoma, Non-Small-Cell Lung
Chromatography, Liquid
Drug Therapy
Feces
In Vitro Techniques
Liposomes*
Liver
Lung
Lung Neoplasms
Mass Spectrometry
Metabolic Networks and Pathways
Metabolism*
Microsomes
Models, Animal
Rabbits*
Tandem Mass Spectrometry
Liposomes

Figure

• 

  Fig. 1 In vitro metabolism of DTX-LP and DTX-IN in different rabbit tissue homogenates and microsomes.(A) Percentage of DTX incubated in rabbit lung homogenates at different time (n=3). (B) Percentage of DTX incubated with rabbit liver homogenates at different time (n=3). (C) Percentage of DTX incubated with rabbit liver microsomes at different time (n=3).

• 

  Fig. 2 Representative chromatograms of DTX-IN in rabbit liver homogenates by ultra-performance liquid chromatography.(A) Total ion chromatogram (TIC) at initial time (0 min). (B) TIC after 2 hours of incubation. (C) Extraction ion chromatogram (EIC) of DTX-IN. (D) EIC of M-2. (E) EIC of Mun.

• 

  Fig. 3 Representative chromatograms of DTX-LP in rabbit liver homogenates by ultra-performance liquid chromatography.Total ion chromatogram (TIC) at initial time (0 min). (B) TIC after 2 hours of incubation. (C) Extraction ion chromatogram (EIC) of DTX-LP. (D) EIC of M-2. (E) EIC of Mun.

• 

  Fig. 4 Tandem mass spectrometry (MS) of DTX, M2 and Mun(A) First order MS of DTX. (B) Secondary MS of DTX. (C) First order MS of M-2. (D) Secondary MS of M-2. (E) First order MS of Mun. (F) Secondary MS of Mun. For B, D and E, the parent ions are [M+Na]+.

• 

  Fig. 5 Representative chromatograms of DTX-IN and DTX-LP in bile juice by ultra-performance liquid chromatography.(A) Total ion chromatogram (TIC) of DTX-IN. (B) Extraction ion chromatogram (EIC) of DTX-IN. (C) EIC of M2 from DTX-IN. (D) TIC of DTX-LP. (E) EIC of DTX-LP. (F) EIC of M-2 from DTX-LP.

• 

  Fig. 6 The proposed structure of Mun.

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