Determining the Drug-Like Properties of Ailanthone, a Novel Chinese Medicine Monomer with Anti-CRPC Activity

Abstract

Approximately 40% of compounds with therapeutic potential cannot be successfully developed into drugs owing to their poor pharmaceutical properties, emphasising the need to profile their drug-like properties as early as possible during preclinical development. This study aimed to evaluate the drug-like properties of ailanthone, a novel Chinese medicine monomer that was shown to have activity against castration-resistant prostate cancer tumour growth and metastasis in our previous study. The drug-like properties detected in the present study included effects on permeability, liver microsome stability, plasma protein binding rate, plasma stability, and human ether-à-go-go-related gene inhibition. Additionally, the following results were obtained: the efflux ratio of ailanthone was > 32 during permeability detection; the half-life and intrinsic clearance (Cl_int) in mouse, rat, and human liver microsomes were > 145 min and < 9.6 µL/min/mg protein, respectively. The Cl_int(liver) of ailanthone was < 38.0, < 17.3, and < 8.6 mL/min/kg body weight in mice, rats, and humans, respectively. The plasma protein binding percentage of ailanthone was 16.6 ± 4.2% in human plasma, with 62.5% remaining at 120 min after incubation. The IC₅₀ value of ailanthone for the human ether-à-go-go-related gene channels was > 30 µM. Collectively, these results and those from our previous study indicate that the pharmacokinetic properties of ailanthone are suitable for the potential development of this compound as an oral or intravenous drug for the treatment of castration-resistant prostate cancer.

Key words

AIL - Simaroubaceae - drug-like properties - LC-MS/MS

• References

• 1 Patridge E, Gareiss P, Kinch MS, Hoyer D. An analysis of FDA-approved drugs: natural products and their derivatives. Drug Discov Today 2016; 21: 204-207
• 2 Kim HM, Kim SJ, Kim HY, Ryu B, Kwak H, Hur J, Choi JH, Jang DS. Constituents of the stem barks of Ailanthus altissima and their potential to inhibit LPS-induced nitric oxide production. Bioorg Med Chem Lett 2015; 25: 1017-1020
• 3 Daga M, Pizzimenti S, Dianzani C, Cucci MA, Cavalli R, Grattarola M, Ferrara B, Scariot V, Trotta F, Barrera G. Ailanthone inhibits cell growth and migration of cisplatin resistant bladder cancer cells through down-regulation of Nrf2, YAP, and c-Myc expression. Phytomedicine 2019; 56: 156-164
• 4 Rosati A, Quaranta E, Ammirante M, Turco MC, Leone A, De Feo V. Quassinoids can induce mitochondrial membrane depolarisation and caspase 3 activation in human cells. Cell Death Differ 2004; 11 (Suppl. 02) S216-S218
• 5 Wang R, Xu Q, Liu L, Liang X, Cheng L, Zhang M, Shi Q. Antitumour activity of 2-dihydroailanthone from the bark of Ailanthus altissima against U251. Pharm Biol 2016; 54: 1641-1648
• 6 He Y, Peng S, Wang J, Chen H, Cong X, Chen A, Hu M, Qin M, Wu H, Gao S, Wang L, Wang X, Yi Z, Liu M. Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer. Nat Commun 2016; 7: 13122
• 7 Peng S, Yi Z, Liu M. Ailanthone: a new potential drug for castration-resistant prostate cancer. Chin J Cancer 2017; 36: 25
• 8 Mohs RC, Greig NH. Drug discovery and development: Role of basic biological research. Alzheimers Dement (N Y) 2017; 3: 651-657
• 9 Tsaioun K, Bottlaender M, Mabondzo A. Alzheimerʼs Drug Discovery Foundation. ADDME–Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective. BMC Neurol 2009; 9 (Suppl. 01) S1
• 10 Stokes NR, Baker N, Bennett JM, Berry J, Collins I, Czaplewski LG, Logan A, Macdonald R, Macleod L, Peasley H, Mitchell JP, Nayal N, Yadav A, Srivastava A, Haydon DJ. An improved small-molecule inhibitor of FtsZ with superior in vitro potency, drug-like properties, and in vivo efficacy. Antimicrob Agents Chemother 2013; 57: 317-325
• 11 Tang SW, Ma XR, Lu J, Zhang Y, Liu M, Wang X. Preclinical toxicology and toxicokinetic evaluation of ailanthone, a natural product against castration-resistant prostate cancer, in mice. Fitoterapia 2019; 136: 104161
• 12 Okunade AL, Bikoff RE, Casper SJ, Oksman A, Goldberg DE, Lewis WH. Antiplasmodial activity of extracts and quassinoids isolated from seedlings of Ailanthus altissima (Simaroubaceae). Phytother Res 2003; 17: 675-677
• 13 Zhuo Z, Hu J, Yang X, Chen M, Lei X, Deng L, Yao N, Peng Q, Chen Z, Ye W, Zhang D. Ailanthone inhibits Huh7 cancer cell growth via cell cycle arrest and apoptosis in vitro and in vivo . Sci Rep 2015; 5: 16185
• 14 Mondal SK, Mondal NB, Banerjee S, Mazumder UK. Determination of drug-like properties of a novel antileishmanial compound: In vitro absorption, distribution, metabolism, and excretion studies. Indian J Pharmacol 2009; 41: 176-181
• 15 Hubatsch I, Ragnarsson EG, Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protoc 2007; 2: 2111-2119
• 16 Reid AM, Juvonen R, Huuskonen P, Lehtonen M, Pasanen M, Lall N. In vitro human metabolism and inhibition potency of verbascoside for CYP enzymes. Molecules 2019; 24: E2191
• 17 Volpp M, Holzgrabe U. Determination of plasma protein binding for sympathomimetic drugs by means of ultrafiltration. Eur J Pharm Sci 2019; 127: 175-184
• 18 Routledge PA. The plasma protein binding of basic drugs. Br J Clin Pharmacol 1986; 22: 499-506
• 19 Di L, Kerns EH, Hong Y, Chen H. Development and application of high throughput plasma stability assay for drug discovery. Int J Pharm 2005; 297: 110-119
• 20 Reed GA. Stability of drugs, drug candidates, and metabolites in blood and plasma. Curr Protoc Pharmacol 2016; 75: 7.6.1-7.6.12
• 21 Kuryshev YA, Brown AM, Wang L, Benedict CR, Rampe D. Interactions of the 5-hydroxytryptamine 3 antagonist class of antiemetic drugs with human cardiac ion channels. J Pharmacol Exp Ther 2000; 295: 614-620
• 22 Weirich J, Antoni H. Rate-dependence of antiarrhythmic and proarrhythmic properties of class I and class III antiarrhythmic drugs. Basic Res Cardiol 1998; 93 (Suppl. 01) 125-132
• 23 Bode G, Olejniczak K. ICH Expert Working Group. ICH topic: the draft ICH S7B step 2: note for guidance on safety pharmacology studies for human pharmaceuticals. Fundam Clin Pharmacol 2002; 16: 105-118
• 24 Baranczewski P, Stanczak A, Sundberg K, Svensson R, Wallin A, Jansson J, Garberg P, Postlind H. Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development. Pharmacol Rep 2006; 58: 453-472
• 25 Wang Y, Xie G, Liu Q, Duan X, Liu Z, Liu X. Pharmacokinetics, tissue distribution, and plasma protein binding study of chicoric acid by HPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1031: 139-145
• 26 Isbell J, Yuan D, Torrao L, Gatlik E, Hoffmann L, Wipfli P. Plasma protein binding of highly bound drugs determined with equilibrium gel filtration of nonradiolabeled compounds and LC-MS/MS detection. J Pharm Sci 2019; 108: 1053-1060
• 27 Jo SH, Youm JB, Lee CO, Earm YE, Ho WK. Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline. Br J Pharmacol 2000; 129: 1474-1480
• 28 Hancox JC, Witchel HJ. Psychotropic drugs, HERG, and the heart. Lancet 2000; 356: 428
• 29 Lennernas H, Palm K, Fagerholm U, Artursson P. Comparison between active and passive drug transport in human intestinal epithelial (Caco-2) cells in vitro and human jejunum in vivo . Int J Pharm 1996; 127: 103-107
• 30 Artursson P, Ungell AL, Löfroth JE. Selective paracellualr permeability in two models of intestinal absorption: cultured monolayers of human intestinal epithelial cells and rat intestinal segments. Pharm Res 1993; 10: 1123-1129
• 31 Zhao C, Ying Z, Hao D, Zhang W, Ying X, Yang G. Investigating the bioavailabilities of olerciamide A via the ratʼs hepatic, gastric and intestinal first-pass effect models. Biopharm Drug Dispos 2019; 40: 112-120
• 32 Jeong H, Lee J, Kim S, Yeo YY, So H, Wu H, Song YS, Jang CY, Kim HD, Kim MJ, Chang M. Hepatic metabolism of Sakuranetin and its modulating effects on cytochrome P450s and UDP-glucuronosyltransferases. Molecules 2018; 23: E1542
• 33 Houston JB. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 1994; 47: 1469-1479
• 34 Huang Z, Ung T. Effect of alpha-1-acid glycoprotein binding on pharmacokinetics and pharmacodynamics. Curr Drug Metab 2013; 14: 226-238
• 35 Howard ML, Hill JJ, Galluppi GR, McLean MA. Plasma protein binding in drug discovery and development. Comb Chem High Throughput Screen 2010; 13: 170-187