Membrane-water partitioning, membrane permeability, and baseline toxicity of the parasiticides ivermectin, albendazole, and morantel.
A comparative hazard assessment of the antiparasitics ivermectin, albendazole, and morantel was performed, with a particular focus on bioavailability and uptake into biological membranes. The experimentally determined liposome-water distribution ratio at pH 7 (D(lipw) (pH 7)) of the positively charged morantel was 100 L/kg lipid. The D(lipw) (pH 7) of albendazole was 3,000 L/kg lipid. The membrane permeability determined with the parallel artificial membrane permeability assay was consistent with predictions from a quantitative structure-activity relationship (QSAR) for morantel but 14-fold lower than predicted for albendazole, which can be rationalized because neutral albendazole is, in fact, zwitterionic and the large dipole moment hinders permeation through hydrophobic membranes. An unusually large molecule, ivermectin was suspected to show decreased bioaccumulation because of its bulkiness, but experimental determination of solubility showed that it was 40-fold less soluble than expected from a QSAR between solubility and the octanol-water partition coefficient. In contrast, its membrane permeability appeared to be typical for a compound of the given hydrophobicity, but it was not possible to determine the membrane-water partition coefficient because of its low solubility and high affinity to the dialysis membrane of the experimental device. The D(lipw) (pH 7) for ivermectin of 2,700 L/kg lipid was calculated with a QSAR model. Morantel and albendazole were baseline toxicants in the bioluminescence inhibition test with Vibrio fischeri and a test for inhibition of photosynthesis in green algae. Only ivermectin exhibited a specific effect toward algae, but the excess toxicity was not very pronounced and might be biased by the uncertainty of the estimated hydrophobicity descriptor. Overall, we did not find any unexpected effect on nontarget endpoints.
Escher
Beate I
BI
Swiss Federal Institute of Aquatic Science and Technology, Eawag, 8600 Dübendorf, Switzerland. escher@eawag.ch
Berger
Cindy
C
Bramaz
Nadine
N
Kwon
Jung-Hwan
JH
Richter
Manuela
M
Tsinman
Oksana
O
Avdeef
Alex
A
D015766:Albendazole / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D002463:Cell Membrane Permeability; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005399:Fishes / Q000378:metabolism; D007559:Ivermectin / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D008081:Liposomes / Q000737:chemistry; D009015:Morantel / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility
D000977:Antiparasitic Agents; D008081:Liposomes; D007559:Ivermectin; D009015:Morantel; D015766:Albendazole