Year: 2025 | Month: December | Volume: 12 | Issue: 12 | Pages: 469-477
DOI: https://doi.org/10.52403/ijrr.20251249
Pharmacokinetic and Toxicological Characterization of Tetrandrine Using in Silico ADMET Modelling
Putri Niat Salma Halawa1, Poppy Anjelisa Zaitun Hasibuan2, Denny Satria3
1Master in Pharmaceutical Sciences Program, 2Department of Pharmacology, 3Department of Pharmaceutical Biology,
Faculty of Pharmacy, Universitas Sumatera Utara, Medan 20155, Indonesia.
Corresponding Author: Poppy Anjelisa Zaitun Hasibuan
ABSTRACT
Tetrandrine, a bis-benzylisoquinoline alkaloid from Stephania tetrandra, is widely investigated as a multitarget anticancer and chemosensitizing candidate, but its developability depends on a clear pharmacokinetic and safety profile. This study assessed tetrandrine using an integrated in silico ADMET workflow (SwissADME, pkCSM, and ADMETlab 3.0) and predicted acute toxicity with GUSAR. Tetrandrine showed high lipophilicity (consensus LogP 5.49; 3.73-6.66 across models) and very low aqueous solubility (ESOL LogS -8.02; Ali LogS -7.76; SILICOS-IT LogS -10.8; pkCSM solubility -3.886 log mol/L), with moderate passive permeability (Caco-2 0.43 log Papp). The BOILED-Egg model indicated a high probability of intestinal absorption with limited blood-brain barrier (BBB) penetration, consistent with low BBB permeability (LogBB -0.618) and low CNS permeability (logPS -2.27). Distribution estimates suggested moderate tissue distribution (Vd -0.624, log scale) and a measurable free fraction in plasma (fu 0.358). P-glycoprotein classification differed between tools, but pkCSM consistently predicted P-gp I/II inhibition. Metabolism models predicted tetrandrine as a substrate of CYP1A2, CYP2C9, CYP2C19, CYP2B6, and CYP3A4, with low inhibitory potential; CYP2D6 substrate status was tool-dependent. Elimination parameters indicated moderate clearance (0.71 log mL/min/kg; 9.238 mL/min/kg) and a predicted half-life of 2.567 h, with no OCT2 substrate liability. GUSAR predicted route-dependent LD50 values of 65.4 mg/kg (IV), 70.9 mg/kg (IP), 121.8 mg/kg (SC), and 708.3 mg/kg (oral). Overall, tetrandrine appears pharmacokinetically challenging, supporting the need for solubility-enhancing formulations and focused non-clinical safety studies.
Keywords: Pharmacokinetics; In silico ADMET; Toxicity; Chemosensitizing agent; Breast cancer.
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