Study on In Vitro Metabolism and In Vivo Pharmacokinetics of Beauvericin

Overview

Journal Toxins (Basel)

Publisher MDPI

Specialty Toxicology

Date 2022 Jul 25

PMID 35878215

Authors

Yu Yuan

Guangpeng Meng

Yuanbo Li

Chunjie Wu

Affiliations

Soon will be listed here.

Abstract

Beauvericin (BEA) is a well-known mycotoxin produced by many fungi, including Beaveria bassiana. The purpose of this study was to evaluate the in vitro distribution and metabolism characteristics as well as the in vivo pharmacokinetic (PK) profile of BEA. The in vitro metabolism studies of BEA were performed using rat, dog, mouse, monkey and human liver microsomes, cryopreserved hepatocytes and plasma under conditions of linear kinetics to estimate the respective elimination rates. Additionally, LC-UV-MSn (n = 1~2) was used to identify metabolites in human, rat, mouse, dog and monkey liver microsomes. Furthermore, cytochrome P450 (CYP) reaction phenotyping was carried out. Finally, the absolute bioavailability of BEA was evaluated by intravenous and oral administration in rats. BEA was metabolically stable in the liver microsomes and hepatocytes of humans and rats; however, it was a strong inhibitor of midazolam 1′-hydroxylase (CYP3A4) and mephenytoin 4′-hydroxylase (CYP2C19) activities in human liver microsomes. The protein binding fraction values of BEA were >90% and the half-life (T1/2) values of BEA were approximately 5 h in the plasma of the five species. The absolute bioavailability was calculated to be 29.5%. Altogether, these data indicate that BEA has great potential for further development as a drug candidate. Metabolic studies of different species can provide important reference values for further safety evaluation.

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References

Buchter C, Koch K, Freyer M, Baier S, Saier C, Honnen S . The mycotoxin beauvericin impairs development, fertility and life span in the nematode Caenorhabditis elegans accompanied by increased germ cell apoptosis and lipofuscin accumulation. Toxicol Lett. 2020; 334:102-109. DOI: 10.1016/j.toxlet.2020.09.016. View

Salim A, Nadri S, Hosseini M, Rokni-Zadeh H, Mohseni M . Protective effect of probiotic Lactobacillus acidophilus against the toxicity of beauvericin mycotoxin on the Caco-2 cell line. Toxicon. 2020; 185:184-187. DOI: 10.1016/j.toxicon.2020.07.003. View

Powell M, Stewart T, Otvos Jr L, Urge L, Gaeta F, Sette A . Peptide stability in drug development. II. Effect of single amino acid substitution and glycosylation on peptide reactivity in human serum. Pharm Res. 1993; 10(9):1268-73. DOI: 10.1023/a:1018953309913. View

Kouri K, Duchen M, Lemmens-Gruber R . Effects of beauvericin on the metabolic state and ionic homeostasis of ventricular myocytes of the guinea pig. Chem Res Toxicol. 2005; 18(11):1661-8. DOI: 10.1021/tx050096g. View

Riley R, Grime K . Metabolic screening in vitro: metabolic stability, CYP inhibition and induction. Drug Discov Today Technol. 2014; 1(4):365-72. DOI: 10.1016/j.ddtec.2004.10.008. View

Lin H, Lee Y, Chen B, Tsai M, Lu J, Chou C . Involvement of Bcl-2 family, cytochrome c and caspase 3 in induction of apoptosis by beauvericin in human non-small cell lung cancer cells. Cancer Lett. 2005; 230(2):248-59. DOI: 10.1016/j.canlet.2004.12.044. View

Noto P, Abbadessa G, Cassone M, Mateo G, Agelan A, Wade J . Alternative stabilities of a proline-rich antibacterial peptide in vitro and in vivo. Protein Sci. 2008; 17(7):1249-55. PMC: 2442003. DOI: 10.1110/ps.034330.108. View

Mikov M, danic M, Pavlovic N, Stanimirov B, Golocorbin-Kon S, Stankov K . The Role of Drug Metabolites in the Inhibition of Cytochrome P450 Enzymes. Eur J Drug Metab Pharmacokinet. 2017; 42(6):881-890. DOI: 10.1007/s13318-017-0417-y. View

Wu Q, Patocka J, Nepovimova E, Kuca K . A Review on the Synthesis and Bioactivity Aspects of Beauvericin, a Mycotoxin. Front Pharmacol. 2018; 9:1338. PMC: 6256083. DOI: 10.3389/fphar.2018.01338. View

10.

Lahoz A, Gombau L, Donato M, Castell J, Gomez-Lechon M . In vitro ADME medium/high-throughput screening in drug preclinical development. Mini Rev Med Chem. 2006; 6(9):1053-62. DOI: 10.2174/138955706778195153. View

11.

Pellegatti M . Preclinical in vivo ADME studies in drug development: a critical review. Expert Opin Drug Metab Toxicol. 2012; 8(2):161-72. DOI: 10.1517/17425255.2012.652084. View

12.

Di L . Strategic approaches to optimizing peptide ADME properties. AAPS J. 2014; 17(1):134-43. PMC: 4287298. DOI: 10.1208/s12248-014-9687-3. View

13.

Meca G, Sospedra I, Soriano J, Ritieni A, Moretti A, Manes J . Antibacterial effect of the bioactive compound beauvericin produced by Fusarium proliferatum on solid medium of wheat. Toxicon. 2010; 56(3):349-54. DOI: 10.1016/j.toxicon.2010.03.022. View

14.

Muttenthaler M, King G, Adams D, Alewood P . Trends in peptide drug discovery. Nat Rev Drug Discov. 2021; 20(4):309-325. DOI: 10.1038/s41573-020-00135-8. View

15.

Tong Y, Liu M, Zhang Y, Liu X, Huang R, Song F . Beauvericin counteracted multi-drug resistant by blocking ABC transporters. Synth Syst Biotechnol. 2017; 1(3):158-168. PMC: 5640798. DOI: 10.1016/j.synbio.2016.10.001. View

16.

Groll A, Townsend R, Desai A, Azie N, Jones M, Engelhardt M . Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4. Transpl Infect Dis. 2017; 19(5). DOI: 10.1111/tid.12751. View

17.

Di L, Kerns E, Carter G . Drug-like property concepts in pharmaceutical design. Curr Pharm Des. 2009; 15(19):2184-94. DOI: 10.2174/138161209788682479. View

18.

Yang Z, Kulkarni K, Zhu W, Hu M . Bioavailability and pharmacokinetics of genistein: mechanistic studies on its ADME. Anticancer Agents Med Chem. 2012; 12(10):1264-80. PMC: 4010305. DOI: 10.2174/187152012803833107. View

19.

Rock B, Foti R . Pharmacokinetic and Drug Metabolism Properties of Novel Therapeutic Modalities. Drug Metab Dispos. 2019; 47(10):1097-1099. DOI: 10.1124/dmd.119.088708. View

20.

Powell M, Grey H, Gaeta F, Sette A, Colon S . Peptide stability in drug development: a comparison of peptide reactivity in different biological media. J Pharm Sci. 1992; 81(8):731-5. DOI: 10.1002/jps.2600810802. View