Biological fate and interaction with cytochromes P450 of the nanocarrier material, d- α-tocopheryl polyethylene glycol 1000 succinate

doi:10.1016/j.apsb.2022.01.014

. 2022 Jul;12(7):3156-3166.

doi: 10.1016/j.apsb.2022.01.014. Epub 2022 Jan 25.

Biological fate and interaction with cytochromes P450 of the nanocarrier material, d- α-tocopheryl polyethylene glycol 1000 succinate

Tianming Ren^{1

2}, Runzhi Li^{1

2}, Liqiang Zhao², J Paul Fawcett¹, Dong Sun^{1

2}, Jingkai Gu^{1

3

2}

Affiliations

¹ Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China.
² Beijing Institute of Drug Metabolism, Beijing 102209, China.
³ State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun 130012, China.

PMID: 35865103
PMCID: PMC9293673
DOI: 10.1016/j.apsb.2022.01.014

Biological fate and interaction with cytochromes P450 of the nanocarrier material, d- α-tocopheryl polyethylene glycol 1000 succinate

Tianming Ren et al. Acta Pharm Sin B. 2022 Jul.

. 2022 Jul;12(7):3156-3166.

doi: 10.1016/j.apsb.2022.01.014. Epub 2022 Jan 25.

Authors

Tianming Ren^{1

2}, Runzhi Li^{1

2}, Liqiang Zhao², J Paul Fawcett¹, Dong Sun^{1

2}, Jingkai Gu^{1

3

2}

Affiliations

¹ Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China.
² Beijing Institute of Drug Metabolism, Beijing 102209, China.
³ State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun 130012, China.

PMID: 35865103
PMCID: PMC9293673
DOI: 10.1016/j.apsb.2022.01.014

Abstract

d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS, also known as vitamin E-TPGS) is a biodegradable amphiphilic polymer prepared by esterification of vitamin E with polyethylene glycol (PEG) 1000. It is approved by the US Food and Drug Administration (FDA) and has found wide application in nanocarrier drug delivery systems (NDDS). Fully characterizing the in vivo fate and pharmacokinetic behavior of TPGS is important to promote the further development of TPGS-based NDDS. However, to date, a bioassay for the simultaneous quantitation of TPGS and its metabolite, PEG1000, has not been reported. In the present study, we developed such an innovative bioassay and used it to investigate the pharmacokinetics, tissue distribution and excretion of TPGS and PEG1000 in rat after oral and intravenous dosing. In addition, we evaluated the interaction of TPGS with cytochromes P450 (CYP450s) in human liver microsomes. The results show that TPGS is poorly absorbed after oral administration with very low bioavailability and that, after intravenous administration, TPGS and PEG1000 are mainly distributed to the spleen, liver, lung and kidney before both being slowly eliminated in urine and feces as PEG1000. In vitro studies show the inhibition of human CYP450 enzymes by TPGS is limited to a weak inhibition of CYP3A4. Overall, our results provide a clear picture of the in vivo fate of TPGS which will be useful in evaluating the safety of TPGS-based NDDS in clinical use and in promoting their further development.

Keywords: Cytochrome P450; Excretion; LC‒MS/MS; Metabolism; Nanocarrier materials; Pharmacokinetics; TPGS; Tissue distribution.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

**Figure 1**
Structures of TPGS and its metabolite PEG1000 (n ∼ 22).

**Figure 2**
Q1 full scan of (A) TPGS and (B) PEG1000 at DP 50 V.

**Figure 3**
Q1 full scan of (A) TPGS and (B) PEG1000 at DP 200 V, TPGS fragment ions and PEG1000 fragment ions (red circle) produced by DP 200 V; Optimizing DP of (C) TPGS-specific fragment ion (m/z 557.4) and (D) PEG1000-specific fragment ion (m/z 221.3).

**Figure 4**
Representative in-source CID-MRM chromatograms of (A) PEG1000 and (B) TPGS.

**Figure 5**
Mass spectra of chromatographic peaks corresponding to PEG1000 and TPGS in (A and B) reference standards and (C and D) a plasma sample collected from a rat 1 h after intravenous injection of TPGS.

**Figure 6**
Mean plasma concentration‒time curves (and inset of lg concentration–time curves) of TPGS and its metabolite PEG1000 after single intravenous 5 mg/kg injections of TPGS to rats (data are means ± SD, n = 6).

**Figure 7**
Tissue distribution of TPGS in rat at 10 min, 30 min, 2 h and 10 h after single intravenous 5 mg/kg injections of TPGS (data are means ± SD, n = 6).

**Figure 8**
Tissue distribution of PEG1000 in rat at 10 min, 30 min, 2 h and 10 h after single intravenous 5 mg/kg injections of TPGS (data are means ± SD, n = 6).

**Figure 9**
Tissue concentration‒time curves of TPGS and its metabolite PEG1000 after a single intravenous 5 mg/kg injections of TPGS (data are means ± SD, n = 6).

**Figure 10**
Cumulative excretion–time curves of (A) TPGS in rat feces, (B) PEG1000 in rat feces, (C) PEG1000 in rat urine and (D) total TPGS and PEG1000 in feces and urine after single intravenous 5 mg/kg injections of TPGS (data are means ± SD, n = 6).

**Figure 11**
Activity‒concentration profiles for the inhibition of human liver CYP450 enzymes by TPGS (data are means ± SD, n = 3).

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References

1. Guo Y.Y., Luo J., Tan S.W., Otieno B.O., Zhang Z.P. The applications of Vitamin E TPGS in drug delivery. Eur J Pharmaceut Sci. 2013;49:175–186. - PubMed
1. Yan A.H., Von Dem Bussche A., Kane A.B., Hurt R.H. Tocopheryl polyethylene glycol succinate as a safe, antioxidant surfactant for processing carbon nanotubes and fullerenes. Carbon. 2007;45:2463–2470. - PMC - PubMed
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1. Zhang Z.P., Tan S.W., Feng S.S. Vitamin E TPGS as a molecular biomaterial for drug delivery. Biomaterials. 2012;33:4889–4906. - PubMed
1. Collnot E.M., Baldes C., Wempe M.F., Kappl R., Huttermann J., Hyatt J.A., et al. Mechanism of inhibition of P-glycoprotein mediated efflux by vitamin E TPGS: influence on ATPase activity and membrane fluidity. Mol Pharm. 2007;4:465–474. - PubMed

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[1] Guo Y.Y., Luo J., Tan S.W., Otieno B.O., Zhang Z.P. The applications of Vitamin E TPGS in drug delivery. Eur J Pharmaceut Sci. 2013;49:175–186. - PubMed

[2] Guo Y.Y., Luo J., Tan S.W., Otieno B.O., Zhang Z.P. The applications of Vitamin E TPGS in drug delivery. Eur J Pharmaceut Sci. 2013;49:175–186. - PubMed

[3] Yan A.H., Von Dem Bussche A., Kane A.B., Hurt R.H. Tocopheryl polyethylene glycol succinate as a safe, antioxidant surfactant for processing carbon nanotubes and fullerenes. Carbon. 2007;45:2463–2470. - PMC - PubMed

[4] Yan A.H., Von Dem Bussche A., Kane A.B., Hurt R.H. Tocopheryl polyethylene glycol succinate as a safe, antioxidant surfactant for processing carbon nanotubes and fullerenes. Carbon. 2007;45:2463–2470. - PMC - PubMed

[5] Yang C.L., Wu T.T., Qi Y., Zhang Z.P. Recent advances in the application of vitamin E TPGS for drug delivery. Theranostics. 2018;8:464–485. - PMC - PubMed

[6] Yang C.L., Wu T.T., Qi Y., Zhang Z.P. Recent advances in the application of vitamin E TPGS for drug delivery. Theranostics. 2018;8:464–485. - PMC - PubMed

[7] Zhang Z.P., Tan S.W., Feng S.S. Vitamin E TPGS as a molecular biomaterial for drug delivery. Biomaterials. 2012;33:4889–4906. - PubMed

[8] Zhang Z.P., Tan S.W., Feng S.S. Vitamin E TPGS as a molecular biomaterial for drug delivery. Biomaterials. 2012;33:4889–4906. - PubMed

[9] Collnot E.M., Baldes C., Wempe M.F., Kappl R., Huttermann J., Hyatt J.A., et al. Mechanism of inhibition of P-glycoprotein mediated efflux by vitamin E TPGS: influence on ATPase activity and membrane fluidity. Mol Pharm. 2007;4:465–474. - PubMed

[10] Collnot E.M., Baldes C., Wempe M.F., Kappl R., Huttermann J., Hyatt J.A., et al. Mechanism of inhibition of P-glycoprotein mediated efflux by vitamin E TPGS: influence on ATPase activity and membrane fluidity. Mol Pharm. 2007;4:465–474. - PubMed

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Biological fate and interaction with cytochromes P450 of the nanocarrier material, d- α-tocopheryl polyethylene glycol 1000 succinate

Affiliations

Biological fate and interaction with cytochromes P450 of the nanocarrier material, d- α-tocopheryl polyethylene glycol 1000 succinate

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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