Evidence for Tissue Toxicity in BALB/c Exposed to a Long-Term Treatment with Oxiranes Compared to Meglumine Antimoniate

Table 1

In silico pharmacokinetic and toxicological parameters for oxirane compounds and meglumine antimoniate.

Predicted properties	Epoxy-α-lapachone	Epoxy-methoxy-lapachol	Meglumine antimoniate	Interpretation
Absorption
Caco2 permeability	1.595	1.584	−0.443	>0,90
Intestinal absorption	100	100	27.93	% absorbed
Skin Permeability	−3.242	−3.249	−2.893	>−2.5 low skin permeability
P-Glycoprotein substrate	Yes	Yes	Yes	Yes/no
P-Glycoprotein inhibitor	No	No	No	Yes/no
Distribution
Volume of distribution	0.201	−0.012	−0.35	Low: <−0.15; high: >0.45
Fraction unbound (human)	0.283	0.392	0.985	0.0 to 1.0
BBB permeability	0.325	0.260	−1.287	Low: <−1/high: >0.30
CNS permeability	−2.087	−2.014	−4.761	Positive: >−2; negative: <−3
Metabolism
CYP3A4 substrate	Yes	No	No	Yes/no
CYP2D6 substrate	No	No	No	Yes/no
CYP3A4 inhibitor	No	No	No	Yes/no
CYP2D6 inhibitor	No	No	No	Yes/no
CYP1A2 inhibitor	Yes	Yes	No	Yes/no
Excretion
Total clearance	0.07	0.197	−0.154	log mL/min/kg
Toxicity
AMES toxicity	No	Yes	No	Yes/no
Max. tolerated dose (human)	0.536	0.925	0.947	log mg/kg/day
Oral Rat Acute Toxicity (LD50)	1.975	1.962	1.184	mol/kg
Oral Rat Chronic Toxicity (LOAEL)	1.728	2.290	1.218	log mg/kg_bw/day
Hepatotoxicity	No	No	No	Yes/no
Skin sensitisation	No	No	No	Yes/no