Pharmacokinetics and Biodistribution of Rhopalurus junceus Scorpion Venom in Tumor-Bearing Mice after Intravenous and Oral Administration

Abstract

Introduction: Rhopalurus junceus scorpion venom has shown potential for anticancer treatment. However, there are no scientific evidence about venom pharmacokinetic (PK) and biodistribution (BD) in tumor-bearing mice. Methods: 131 I-labeled venom was administrated by intravenous (IV) and oral (PO) routes at the single dose of 12.5 mg/kg. Mice were sacrificed and blood samples, major organs, and tumor were taken at 10, 20, 40, 90, 180, 300, 480, and 1440 min. Results: For IV route, maximum peak concentration (C max ), elimination half-lives, total body clearance (CL), distribution volume (V d ), mean residence time (MRT), and area under curve (AUC) were 21.77 ± 2.45 %Dosis·h/mL, 12.65 ± 2.1 h, 4.59 ± 0.23 mL/h, 83.80 ± 12 mL, 12.49 ± 2.71 h, and 21.77 ± 2.45 %Dosis·h/mL, respectively. For PO route, they were 0.60 ± 0.07 %Dosis·h/mL, 9.33 ± 1.35 h, 36.94 ± 4.01 mL/h, 497.33 ± 30 mL, 12.40 ± 1.87 h, and 6.89 ± 1.18 %Dosis·h/mL, respectively. PK parameters (C max , CL, V d , and AUC) showed significant differences between IV and PO routes. Bioavailability was 31.6 ± 4% for PO dose. Kidney, stomach, liver, and lung for IV and stomach, kidney, spleen, and lung for PO routes showed the major uptakes for 131 Ilabeled venom. In tumor tissue, after the maximum uptake for both routes, there was a consistent behavior of radioactivity respect to the major organs during the first 480 min. Conclusion: The PK and BD of R. junceus venom in mice depend on the administration route. These data represent a starting point for future experiments with this scorpion venom in experimental models of cancer.

Voltage-Gated K+/Na+ Channels and Scorpion Venom Toxins in Cancer

“…In only two cases (B. martensii and R. junceus), the scientific results correlate with the experiences in traditional medicine and with the low toxicity recognized in toxicological experiments in mice (Wang and Ji, 2005;Diaz-Garcia et al, 2019a;Dıáz-Garcıá et al, 2019b). The anticancer effect of B. martensii scorpion venom has been tested successfully against human glioma U251-MG by using rodent xenograft models (Wang and Ji, 2005).…”

“…Likewise, in vivo toxicological studies have been carried out, using R. junceus venom administered through intraperitoneal (10 mg/kg) or oral (2,000 mg/kg) routes, and toxic effects have not been observed (Garcia-Gomez et al, 2011;Lagarto et al, 2020). Pharmacokinetic and biodistribution studies carried out on breast tumor-bearing mice administered with a single dose (12.5 mg/kg), by intravenous or oral routes, showed that medium residence time (MRT) of venom in tumor tissue was higher than in the remaining organs tested, suggesting a high selectivity for tumor tissue, adding to their antitumor effect (Diaz-Garcia et al, 2019a). Additionally, breast tumor-bearing mice injected intraperitoneally with ten consecutive doses of R. junceus venom (3.2 mg/kg), showed reduced tumor progression and reduction of Ki67 and CD31 tumor markers, confirming its anticancer potential (Dıáz-Garcıá et al, 2019b).…”

Therapeutic Anticancer Uses of the Active Principles of “Rhopalurus junceus” Venom

“…The studies included for qualitative analysis were the following: Garcia-Gomez et al 2011 [ 1 ], Rodriguez-Ravelo et al 2013 [ 8 ], Diaz-Garcia et al 2013 [ 2 ], Rodriguez-Ravelo et al 2015 [ 9 ], Diaz-Garcia et al 2015 [ 10 ], Giovannini, C. et al 2017 [ 11 ], Diaz-Garcia et al 2017 [ 12 ], Diaz-Garcia et al 2019 [ 3 ], Lagarto et al 2020 [ 4 ], Diaz-Garcia et al 2019 [ 13 ], Di Lorenzo et al 2012 [ 14 ], Yglesias-Rivera et al 2019 [ 15 ], and Lozano-Trujillo et al 2020 [ 16 ].…”

“…The increase in p53 led to an upregulation of bax and caspase 3 and to a downregulation of bcl-2. The increase in the bax/bcl-2 ratio activated the mitochondrial pathway of apoptosis with the release of cytochrome c (Cyt c) and the activation of caspase cascades (3,6,7), which led to the proteolytic breakdown of important cytoplasmic and nuclear substrates [17].…”

“…The cancer cell lines primarily studied were hematopoietic and epithelial lines (pulmonary, mammary, hepatic, and cervix). Recent studies of 2019 and 2020 investigated the pharmacokinetics, pharmacodynamics, and teratogenic effects of the venom [ 3 , 4 ].…”