Pesticide Encapsulation at the Nanoscale Drives Changes to the Hydrophobic Partitioning and Toxicity of an Active Ingredient

Given the costs associated with designing novel active ingredients, new formulations focus on the use of other ingredients to modify existing formulations. Nanosized encapsulated pesticides offer a variety of enhanced features including controlled release and improved efficacy. Despite the presence of nanosized capsules in current-use pesticide formulations, the analytical and toxicological implications of encapsulation are uncertain. To explore this issue quantitatively, we fractionated the capsules of a commercially available encapsulated insecticide formulation (γ-cyhalothrin active ingredient) into two size ranges: a large fraction (LF), with an average hydrodynamic diameter (HDD) of 758 nm, and a small fraction (SF), with an average HDD of 449 nm. We developed a novel extraction method demonstrating a time-dependent inhibition of γ-cyhalothrin from capsules for up to 48 h. An acute immobilization test with a freshwater macroinvertebrate (Ceriodaphnia dubia) revealed that the SF was significantly more toxic than both the LF and the free γ-cyhalothrin treatment (EC50 = 0.18 µg/L, 0.57 µg/L, and 0.65 µg/L, respectively). These findings highlight that encapsulation of γ-cyhalothrin mitigates hydrophobic partitioning in a time-dependent manner and influences toxicity in a size-dependent manner. Recognizing the analytical and toxicological nuances of various nanosized capsules can contribute to innovation in pesticide formulations and may lead to more comprehensive pesticide regulation.

Download Full-text

Comprehensive Investigation of Stereoselective Food Drug Interaction Potential of Resveratrol on Nine P450 and Six UGT Isoforms in Human Liver Microsomes

Pharmaceutics ◽

10.3390/pharmaceutics13091419 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1419

Author(s):

Seung-Bae Ji ◽

So-Young Park ◽

Subin Bae ◽

Hyung-Ju Seo ◽

Sin-Eun Kim ◽

...

Keyword(s):

Drug Interaction ◽

Human Liver ◽

Liver Microsomes ◽

Cytochrome P450s ◽

Human Liver Microsomes ◽

Time Dependent ◽

Dependent Manner ◽

Dependent Inhibition ◽

Drug Inhibition ◽

Time Dependent Inhibition

The stereoselectivity of the food drug inhibition potential of resveratrol on cytochrome P450s and uridine 5′-diphosphoglucuronosyl transferases was investigated in human liver microsomes. Resveratrol enantiomers showed stereoselective inhibition of CYP2C9, CYP3A, and UGT1A1. The inhibitions of CYP1A2, CYP2B6, and CYP2C19 by resveratrol were stereo-nonselective. The estimated Ki values determined for CYP1A2 were 13.8 and 9.2 μM for trans- and cis-resveratrol, respectively. Trans-resveratrol noncompetitively inhibited CYP3A and UGT1A1 activities with Ki values of 23.8 and 27.4 μM, respectively. Trans-resveratrol inhibited CYP1A2, CYP2C19, CYP2E1, and CYP3A in a time-dependent manner with Ki shift values >2.0, while cis-resveratrol time-dependently inhibited CYP2C19 and CYP2E1. The time-dependent inhibition of trans-resveratrol against CYP3A4, CYP2E1, CYP2C19, and CYP1A2 was elucidated using glutathione as a trapping reagent. This information helped the prediction of food drug interaction potentials between resveratrol and co-administered drugs which are mainly metabolized by UGT1A1, CYP1A2, CYP2C19, CYP2E1, and CYP3A.

Download Full-text

Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes

Pharmaceutics ◽

10.3390/pharmaceutics13030371 ◽

2021 ◽

Vol 13 (3) ◽

pp. 371

Author(s):

Hyung-Ju Seo ◽

Seung-Bae Ji ◽

Sin-Eun Kim ◽

Gyung-Min Lee ◽

So-Young Park ◽

...

Keyword(s):

Human Liver ◽

Liver Microsomes ◽

Hepatoprotective Activity ◽

Human Liver Microsomes ◽

Time Dependent ◽

Dependent Manner ◽

Dependent Inhibition ◽

Night Sweats ◽

Gomisin A ◽

Time Dependent Inhibition

Schisandra chinensis has been widely used as a traditional herbal medicine to treat chronic coughs, fatigue, night sweats, and insomnia. Numerous bioactive components including lignans have been identified in this plant. Lignans with a dibenzocyclooctadiene moiety have been known to possess anti-cancer, anti-inflammatory, and hepatoprotective activity. Fragmentary studies have reported the ability of some lignans to modulate some cytochrome P450 (P450) enzymes. Herein, we investigated the drug interaction potential of six dibenzocyclooctadiene lignans (schisandrin, gomisin A, B, C, and N, and wuweizisu C) on nine P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) and six uridine 5′-diphosphoglucuronosyl transferase (UGT) enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) using human liver microsomes. We found that lignans with one or two methylenedioxyphenyl groups inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 activities in a time- and concentration-dependent like their CYP3A inhibition. In comparison, these lignans do not induce time-dependent inhibition of CYP1A2, CYP2A6, and CYP2D6. The time-dependent inhibition of gomisin A against CYP2C8, CYP2C19, and CYP3A4 was also elucidated using glutathione as a trapping reagent of reactive carbene metabolites given that gomisin A strongly inhibits these P450 enzymes in a time-dependent manner. A glutathione conjugate of gomisin A was generated in reactions with human recombinant CYP2C8, CYP2C19, and CYP3A4. This suggests that the time-dependent inhibition of gomisin A against CYP2C8, CYP2C9, and CYP3A4 is due to the production of carbene reactive metabolite. Six of the lignans we tested inhibited the activities of six UGT to a limited extent (IC50 > 15 μM). This information may aid the prediction of possible drug interactions between Schisandra lignans and any co-administered drugs which are mainly metabolized by P450s.

Download Full-text

Evaluations of In Vitro Metabolism, Drug–Drug Interactions Mediated by Reversible and Time-Dependent Inhibition of CYPs, and Plasma Protein Binding of MMB4 DMS

International Journal of Toxicology ◽

10.1177/1091581813487226 ◽

2013 ◽

Vol 32 (4_suppl) ◽

pp. 75S-87S ◽

Cited By ~ 1

Author(s):

S. Peter Hong ◽

Bozena D. Lusiak ◽

Brian L. Burback ◽

Jerry D. Johnson

Keyword(s):

Protein Binding ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Liver Microsomes ◽

Time Dependent ◽

Mass Spectrometry Analysis ◽

Dependent Manner ◽

Reversible Inhibition ◽

Dependent Inhibition ◽

Time Dependent Inhibition

1,1′-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Drug metabolism and plasma protein binding for MMB4 DMS were examined using various techniques and a wide range of species. When 14C-MMB4 DMS was incubated in liver microsomes, 4-pyridine aldoxime (4-PA) and an additional metabolite were detected in all species tested. Identity of the additional metabolite was postulated to be isonicotinic acid (INA) based on liquid chromatography with a tandem mass spectrometry analysis, which was confirmed by comparison with authentic INA. Formation of INA was dependent on species, with the highest level found in monkey liver microsomes. The MMB4 DMS exhibited reversible inhibition in a concentration-dependent manner toward cytochrome P450 1A2 (CYP1A2), CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes showing the highest inhibition for CYP2D6. Human recombinant CYPs were used to evaluate inhibitory curves more adequately and determine detailed kinetic constants for reversible inhibition and potential time-dependent inhibition (TDI). The MMB4 DMS exhibited reversible inhibition toward human-recombinant CYP2D6 with an inhibition constant ( Ki) value of 66.6 µmol/L. Based on the kinact/ KI values, MMB4 DMS was found to exhibit the most potent TDI toward CYP2D6. The MMB4 DMS at 5 different concentrations was incubated in plasma for 5 hours using an equilibrium dialysis device. For all species tested, there were no concentration-dependent changes in plasma protein binding, ranging from 10% to 17%. These results suggest that MMB4 was not extensively bound to plasma protein, and there were no overt species-related differences in the extent of MMB4 bound to plasma protein.

Download Full-text