Abstract
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 (Dlipw (pH 7)) of the positively charged morantel was 100 L/kg lipid. The Dlipw (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 Dlipw (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.
| Original language | English |
|---|---|
| Pages (from-to) | 909-918 |
| Number of pages | 10 |
| Journal | Environmental Toxicology and Chemistry |
| Volume | 27 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2008 Apr 1 |
| Externally published | Yes |
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Keywords
- Aquatic organism
- Baseline toxicity
- Environmental risk assessment
- Quantitative structure-activity relationship
- Veterinary pharmaceuticals
ASJC Scopus subject areas
- Environmental Science(all)
- Environmental Chemistry
- Toxicology
- Health, Toxicology and Mutagenesis
Cite this
Membrane-water partitioning, membrane permeability, and baseline toxicity of the parasiticides ivermectin, albendazole, and morantel. / Escher, Beate I.; Berger, Cindy; Bramaz, Nadine; Kwon, Jung-Hwan; Richter, Manuela; Tsinman, Oksana; Avdeef, Alex.
In: Environmental Toxicology and Chemistry, Vol. 27, No. 4, 01.04.2008, p. 909-918.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Membrane-water partitioning, membrane permeability, and baseline toxicity of the parasiticides ivermectin, albendazole, and morantel
AU - Escher, Beate I.
AU - Berger, Cindy
AU - Bramaz, Nadine
AU - Kwon, Jung-Hwan
AU - Richter, Manuela
AU - Tsinman, Oksana
AU - Avdeef, Alex
PY - 2008/4/1
Y1 - 2008/4/1
N2 - 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 (Dlipw (pH 7)) of the positively charged morantel was 100 L/kg lipid. The Dlipw (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 Dlipw (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.
AB - 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 (Dlipw (pH 7)) of the positively charged morantel was 100 L/kg lipid. The Dlipw (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 Dlipw (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.
KW - Aquatic organism
KW - Baseline toxicity
KW - Environmental risk assessment
KW - Quantitative structure-activity relationship
KW - Veterinary pharmaceuticals
UR - http://www.scopus.com/inward/record.url?scp=42049107987&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=42049107987&partnerID=8YFLogxK
U2 - 10.1897/07-427.1
DO - 10.1897/07-427.1
M3 - Article
C2 - 18333693
AN - SCOPUS:42049107987
VL - 27
SP - 909
EP - 918
JO - The BMJ
JF - The BMJ
SN - 0730-6512
IS - 4
ER -