Effects Of Piperonyl Butoxide Research Articles

Susceptibility of Anopheles gambiae from C\xf4te d\u2019Ivoire to insecticides used on insecticide-treated nets: evaluating the additional entomological impact of piperonyl butoxide and chlorfenapyr

BackgroundPyrethroid-treated mosquito nets are currently the mainstay of vector control in Côte d’Ivoire. However, resistance to pyrethroids has been reported across the country, limiting options for insecticide resistance management due to the paucity of alternative insecticides. Two types of insecticide-treated nets (ITNs), ITNs with pyrethroids and the synergist piperonyl butoxide (PBO), and Interceptor®G2 nets, a net treated with a combination of chlorfenapyr and alpha-cypermethrin, are believed to help in the control of pyrethroid-resistant mosquitoes.MethodsThe susceptibility of Anopheles gambiae sensu lato (s.l.) to pyrethroid insecticides with and without pre-exposure to PBO as well as to chlorfenapyr was investigated in fifteen sites across the country. Susceptibility tests were conducted on 2- to 4-day old adult female An. gambiae s.l. reared from larval collections. The resistance status, intensity, and effects of PBO on mortality after exposure to different concentrations of deltamethrin, permethrin and alpha-cypermethrin were determined using WHO susceptibility test kits. In the absence of a WHO-recommended standard protocol for chlorfenapyr, two interim doses (100 and 200 µg/bottle) were used to test the susceptibility of mosquitoes using the CDC bottle assay method.ResultsPre-exposure to PBO did not result in full restoration of susceptibility to any of the three pyrethroids for the An. gambiae s.l. populations from any of the sites surveyed. However, PBO pre-exposure did increase mortality for all three pyrethroids, particularly deltamethrin (from 4.4 to 48.9%). Anopheles gambiae s.l. from only one site (Bettie) were susceptible to chlorfenapyr at the dose of 100 µg active ingredient (a.i.)/bottle. At the dose of 200 µg (a.i.)/bottle, susceptibility was only recorded in 10 of the 15 sites.ConclusionLow mosquito mortality was found for pyrethroids alone, and while PBO increased mortality, it did not restore full susceptibility. The vector was not fully susceptible to chlorfenapyr in one third of the sites tested. However, vector susceptibility to chlorfenapyr seems to be considerably higher than for pyrethroids alone or with PBO. These data should be used cautiously when making ITN procurement decisions, noting that bioassays are conducted in controlled conditions and may not fully represent field efficacy where the host-seeking behaviours, which include free-flying activity are known to enhance pro-insecticide chlorfenapyr intoxication to mosquitoes.

Effects of piperonyl butoxide on exploratory behaviour in female mice.

Previous studies reported that piperonyl butoxide (PBO) induces adverse effects on exploratory behaviour in male mice. However, no consistent effects of PBO treatment were observed in female mice. This study aimed to evaluate PBO's neurobehavioral effects in female mice. Female mice were exposed to PBO through diet to provide levels of 0 (control), 0.025%, 0.1%, and 0.4% from 5 to 12 weeks of age, and selected behavioural parameters were measured. The average female body weight showed no significant effect from PBO treatment through the experimental periods. Regarding multiple-T water maze performance at 10 weeks of age, no significant effect caused by PBO treatment was observed. Exploratory behaviour examination of 8-week-old female mice indicated that the average speed declined in a significant dose-related manner, and the longitudinal pattern indicated a significant difference between the control and high-dose groups. For exploratory behaviour examination at 11 weeks of age, the total exploration distance shortened in a significant dose-related manner, and the average speed declined similarly. These longitudinal patterns showed significant differences between the control and high-dose groups. The PBO dose levels in this study produced several adverse effects on exploratory behaviour in female mice.

Piperonyl Butoxide: An Enhancing Arsenal for an Adomant Foe

Vector control using treated nets and recently industrially long lasting insecticidal nets (LLINs) have played a vital role in malaria control globally. The emergence of insecticides resistance among malaria vector against pyrethroids has raised a concern over achieved a milestone. Different insecticides resistance mechanisms have evolved against pyrethroids. This has given mosquitoes an opportunity to increase survivor fitness. The incorporation of synegistic effect of Piperonyl Butoxide (PBO) in LLINs has shown a significant impact in areas with pyrethroid resistant malaria vectors than LLIN without PBO. LLINs with PBO for management of resistance can revive pyrethroid strength against resistant malaria vectors. There is a necessity for National malaria control and other NGOs in Africa distributing LLINs to distribute nets with pyrethroids and PBO.

Effect of Piperonyl Butoxide and Silver Nitrate on Degradation Pathways of n-octadecane by Fusarium sp. F092

The aliphatic fraction is usually the largest component in crude oil. Its removal from oil contaminated fields has become an environmental priority and been considered useful for enhancing recovery. Our previous studies reported the isolation of Fusarium sp. F092 based on the ability to degrade chrysene. It also could degrade crude oils and their aliphatics fractions. However, aliphatic degradative pathways in crude oil have not been clearly understood. The identification of aliphatic metabolite pathways using a representative compound n -octadecane was carried out in this study, as well as the effect of Piperonyl Butoxide (PB) and Silver Nitrate (AgNO 3 ) on the degradation of n -octadecane and its metabolite. We determined that Fusarium sp. F092 had ability to break down n -Octadecane from about 125 to 13 mg L -1 after 60 days incubation. During degradation, several metabolite products could be detected and identified to form carboxylic acid groups. By the addition of PB and AgNO 3 , inhibitor of monooxgenase and dioxygenase enzymes, Fusarium sp. F092 had ability to convert n-octadecane to form alkyl hydroperoxides via terminal oxidation pathway with involving a dioxygenase

Effect of Piperonyl Butoxide on the Toxicity of Four Classes of Insecticides to Navel Orangeworm (Amyelois transitella) (Lepidoptera: Pyralidae).

Amyelois transitella (Walker) (Lepidoptera: Pyralidae), the navel orangeworm, is a highly polyphagous economic pest of almond, pistachio, and walnut crops in California. Increasing demand for these crops and their rising economic value has resulted in substantial increases of insecticide applications to reduce damage to acceptable levels. The effects of piperonyl butoxide (PBO), a methylenedioxyphenyl compound that can act as a synergist by inhibiting cytochrome P450-mediated detoxification on insecticide metabolism by A. transitella, were examined in a series of feeding bioassays with first-instar A. transitella larvae from a laboratory strain. PBO, however, can have a variety of effects on metabolism, including inhibition of glutathione-S-transferases and esterases and induction of P450s. In our study, PBO synergized the toxicity of acetamiprid, λ-cyhalothrin, and spinosad, suggesting possible involvement of P450s in their detoxification. In contrast, PBO interacted antagonistically with the organophosphate insecticide chlorpyrifos, reducing its toxicity, an effect consistent with inhibition of P450-mediated bioactivation of this pesticide. The toxicity of the anthranilic diamide insecticide chlorantraniliprole was not altered by PBO, suggestive of little or no involvement of P450-mediated metabolism in its detoxification. Because a population of navel orangeworm in Kern County, CA, has already acquired resistance to the pyrethroid insecticide bifenthrin through enhanced P450 activity, determining the effect of adding a synergist such as PBO on detoxification of all insecticide classes registered for use in navel orangeworm management can help to develop rotation practices that may delay resistance acquisition or to implement alternative management practices where resistance is likely to evolve.

Effects of piperonyl butoxide on the toxicity of the organophosphate temephos and the role of esterases in the insecticide resistance of Aedes aegypti.

The effects of piperonyl butoxide (PBO) on the toxicity of the organophosphate temephos (TE) and the role of esterases in the resistance of Aedes aegypti to this insecticide were evaluated. A. aegypti L4 larvae susceptible and resistant to TE were pre-treated with PBO solutions in acetone at concentrations of 0.125, 0.25, 0.5, 1, and 2% for 24h and subsequently exposed to a diagnostic concentration of 0.02 mg/L aqueous TE solution. The esterase activity of the larvae extracts pre-treated with varying PBO concentrations and exposed to TE for three time periods was determined. At concentrations of 0.25, 0.5, 1, and 2%, PBO showed a significant synergistic effect with TE toxicity. High levels of esterase activity were associated with the survival of A. aegypti L4 larvae exposed to TE only. The results of the biochemical assays suggest that PBO has a significant inhibitory effect on the total esterase activity in A. aegypti larvae.

Analysis of putative inhibitors of anthelmintic resistance mechanisms in cattle gastrointestinal nematodes

Effects of the cytochrome P450 inhibitor piperonyl butoxide and the P-glycoprotein inhibitor verapamil on the efficacy of ivermectin and thiabendazole were studied in vitro in susceptible and resistant isolates of the cattle parasitic nematodes Cooperia oncophora and Ostertagia ostertagi. The effects of combined use of drug and piperonyl butoxide/verapamil, respectively, were investigated in the Egg Hatch Assay, the Larval Development Assay and the Larval Migration Inhibition Assay. The effects of piperonyl butoxide and verapamil as inhibitors of thiabendazole and ivermectin responses were particularly marked for larval development, where both inhibitors were able to completely eliminate all differences between susceptible and resistant isolates. Even the lowest concentrations of anthelmintics used in combination with inhibitors caused complete inhibition of development. Differences and/or similarities among responses in different isolates were only obtained in the two other assays: in the Egg Hatch Assay piperonyl butoxide caused a shift in concentration–response curves obtained with thiabendazole to the left for all isolates tested, changing relative differences between isolates. In contrast, an effect of verapamil in the Egg Hatch Assay was only apparent for benzimidazole-resistant isolates. In the Larval Migration Inhibition Assay only ivermectin was tested and piperonyl butoxide shifted the concentration–response curves for all isolates to the left, again eliminating differences in EC50 values between susceptible and resistant isolates. This was not the case using verapamil as an inhibitor, where curves for both susceptible and benzimidazole-resistant isolates shifted to the left in Ostertagia isolates. In Cooperia the picture was more complex with ivermectin-resistant isolates showing a larger shift than the susceptible isolate. Single nucleotide polymorphisms in the β-tubulin isotype 1 gene were investigated. Significantly increased frequencies of resistance-associated alleles were observed for the codons 167 and 200 in one benzimidazole-resistant isolate but not in an isolate selected for benzimidazole resistance at an early stage of selection.

Elevation of cell proliferation via generation of reactive oxygen species by piperonyl butoxide contributes to its liver tumor-promoting effects in mice

Piperonyl butoxide (PBO) is a pesticide synergist used with pyrethroids as a domestic insecticide, and it acts as a non-genotoxic hepatocarcinogen in rats and mice. To clarify whether oxidative stress is involved in the liver tumor-promoting effect of PBO in mice, male mice were subjected to two-thirds partial hepatectomy, followed by N-diethylnitrosamine (DEN) treatment, and given a diet containing 0.6% PBO for 25 weeks. The incidences of cytokeratin (CK) 8/18-positive foci, adenomas, and carcinomas significantly increased in the DEN + PBO group compared with the DEN-alone group. The PCNA-positive ratio significantly increased in non-tumor hepatocytes, CK8/18-positive foci and adenomas in the DEN + PBO group compared with the DEN-alone group. PBO increased reactive oxygen species (ROS) production in microsomes but did not change oxidative DNA damage as assessed by 8-hydroxydeoxyguanosine (8-OHdG). In real-time RT-PCR, PBO upregulated the expression of genes related to metabolism, such as Cytochrome P450 1a1, 2a5, and 2b10, and metabolic stress, such as Por and Nqo1, but downregulated Egfr and Ogg1. PBO also increased early response genes downstream of mitogen-activated protein kinase (MAPK), such as c-Myc that is induced by excessive ROS production, and G1/S transition-related genes, such as E2f1 and Ccnd1. Thus, PBO can generate ROS via the metabolic pathway without any induction of oxidative DNA damage, activate cell growth, increase c-Myc- and E2F1-related pathways, and act as a liver tumor promoter of DEN-induced hepatocarcinogenesis in mice.

Effects of piperonyl butoxide on spontaneous behavior in F1-generation mice

Piperonyl butoxide was given in the diet to provide levels of 0 (control), 0.02%, 0.06%, and 0.18% from 5 weeks of age of the F(0) generation to 12 weeks of age of the F(1) generation in mice. Select reproductive and neurobehavioral parameters were then measured. In exploratory behavior in the F(0) generation, vertical time of adult females increased significantly in a dose-related manner. In behavioral developmental parameters, cliff avoidance was delayed significantly in the high-dose group in male offspring, and this effect was significantly dose-related. In female offspring, surface righting was significantly delayed in the high-dose group, and this effect was significantly dose-related. In spontaneous behavior in the F(1) generation, females showed more activities in some variables in the high-dose group. Dose levels of piperonyl butoxide used in the present study produced several adverse effects in neurobehavioral parameters in mice.

Effects of Piperonyl Butoxide and Tetramethrin Combinations on Biological Activities of Selected Synthetic Pyrethroid Insecticides against Different Housefly (Musca domestica L., Diptera: Muscidae) Populations

Piperonyl butoxide (PBO), a methylenedioxyphenyl compound, is primarily used as a synergist in combination with space spray, residual and admixture products for the control of insect pests in or around domestic and commercial premises, especially food preparation areas. Also, tetramethrin is known as a knockdown agent on target organism and it is generally used with piperonyl butoxide. In this study, effects of piperonyl butoxide and tetramethrin combinations on biological activities of synthetic pyrethroids, cypermethrin, deltamethrin, and permethrin against different housefly (Musca domestica Linnaeus, 1758) populations were evaluated. In addition, the biological efficiency of the insecticides used in the study, insecticide + PBO and insecticide + PBO + tetramethrin combinations, against the WHO standard sensitive housefly population and housefly populations collected from different parts of Turkey were compared. Results showed that PBO extensively promoted the ratio of knockdown and killing effect values of the insecticides. The results also indicated that PBO and PBO + tetramethrin combinations moderately reduced the knockdown effect times of all formulation in all housefly populations. The knockdown effect times were more decreased by insecticide + PBO + tetramethrin combinations than insecticides that are used alone and insecticide + PBO combinations.

Whole‐sediment toxicity identification evaluation tools for pyrethroid insecticides: I. Piperonyl butoxide addition

Piperonyl butoxide (PBO) is a synergist used in some pyrethroid and pyrethrin pesticide products and has been used in toxicity identification evaluations (TIEs) of water samples to indicate organophosphate or pyrethroid-related toxicity. Methods were developed and validated for use of PBO as a TIE tool in whole-sediment testing to help establish if pyrethroids are the cause of toxicity observed in field-collected sediments. Pyrethroid toxicity was increased slightly more than twofold in 10-d sediment toxicity tests with Hyalella azteca exposed to 25 microg/L of PBO in the overlying water. This concentration was found to be effective for sediment TIE use, but it is well below that used in previous water and pore-water TIEs with PBO. The effect of PBO on the toxicity of several nonpyrethroids also was tested. Toxicity of the organophosphate chlorpyrifos was reduced by PBO, and the compound had no effect on toxicity of cadmium, DDT, or fluoranthene. Mixtures of the pyrethroid bifenthrin and chlorpyrifos were tested to determine the ability of PBO addition to identify pyrethroid toxicity when organophosphates were present in a sample. The PBO-induced increase in pyrethroid toxicity was not seen when chlorpyrifos was present at or above equitoxic concentrations with the pyrethroid. In the vast majority of field samples, however, the presence of chlorpyrifos does not interfere with use of PBO to identify pyrethroid toxicity. Eleven field sediments or soils containing pyrethroids and/or chlorpyrifos were used to validate the method. Characterization of the causative agent as determined by PBO addition was consistent with confirmation by chemical analysis and comparison to known toxicity thresholds in 10 of the 11 sediments.

Toxicity of Aflatoxin B1 to Helicoverpa zea and Bioactivation by Cytochrome P450 Monooxygenases

Infestation of corn (Zea mays) by corn earworm (Helicoverpa zea) predisposes the plant to infection by Aspergillus fungi and concomitant contamination with the carcinogenic mycotoxin aflatoxin B1 (AFB1). Although effects of ingesting AFB1 are well documented in livestock and humans, the effects on insects that naturally encounter this mycotoxin are not as well defined. Toxicity of AFB1 to different stages of H. zea (first, third, and fifth instars) was evaluated with artificial diets containing varying concentrations. Although not acutely toxic at low concentrations (1-20 ng/g), AFB1 had significant chronic effects, including protracted development, increased mortality, decreased pupation rate, and reduced pupal weight. Sensitivity varied with developmental stage; whereas intermediate concentrations (200 ng/g) caused complete mortality in first instars, this same concentration had no detectable adverse effects on larvae encountering AFB1 in fifth instar. Fifth instars consuming AFB1 at higher concentrations (1 microg/g), however, displayed morphological deformities at pupation. That cytochrome P450 monooxygenases (P450s) are involved in the bioactivation of aflatoxin in this species is evidenced by the effects of piperonyl butoxide (PBO), a known P450 inhibitor, on toxicity; whereas no fourth instars pupated in the presence of 1 mug/g AFB1 in the diet, the presence of 0.1% PBO increased the pupation rate to 71.7%. Pupation rates of both fourth and fifth instars on diets containing 1 mug/g AFB1 also increased significantly in the presence of PBO. Effects of phenobarbital, a P450 inducer, on AFB1 toxicity were less dramatic than those of PBO. Collectively, these findings indicate that, as in many other vertebrates and invertebrates, toxicity of AFB1 to H. zea results from P450-mediated metabolic bioactivation.

Effects of Piperonyl Butoxide on the Metabolism of DEF S,S,S-Tributyl Phosphorotrithioate) in Fingerling Channel Catfish

The present study was undertaken to investigate the significance of monooxygenases in bioactivation of DEF to a more effective anticholinesterase in fish. Channel catfish were exposed via the water column for 20 h to piperonyl butoxide (PBO) followed by a 4-h exposure to the organophosphate defolient DEF (concurrent with the PBO). Acetylcholinesterase (AChE) and aliesterases (ALiEs) activities were determined at 0 and 12 h after the exposure period. Inhibition of brain, liver, and plasma AChE activity by DEF was antagonized by PBO; muscle AChE was not inhibited by DEF. Piperonyl butoxide did not antagonize the inhibition of liver or plasma ALiEs by DEF. These results suggest that PBO retards the formation of the metabolite(s) of DEF that inhibit AChE, and that DEF is an effective inhibitor of ALiEs without metabolic activation.

Evaluation of Novel Insecticides for Control of Dengue Vector <I>Aedes aegypti</I> (Diptera: Culicidae)

Insecticides are one of the major tools for controlling vector populations and for reducing the transmission of human pathogens. However, there are few new insecticides being developed and marketed for vector control. Herein, we report on the toxicity of six novel insecticides to both adult and larval Aedes aegypti (L). and the toxicity of three novel insect growth regulators (IGRs) to larvae. Four insecticides were highly or moderately toxic to larvae with LC50 values of 16 (chlorfenapyr), 70 (hydramethylnon), 79 (indoxacarb), and 84 ng/ml (imidacloprid). Diafenthiuron and chlorfenapyr were moderately toxic to adult mosquitoes with LC50 values of 13 and 92 ng/cm2, respectively. Imidacloprid was strongly synergized by piperonyl butoxide (PBO) in Ae. aegypti adults, suggesting that neonicotinoids are intrinsically very toxic to adult mosquitoes (in the absence of detoxification). The effect of PBO on the toxicity in adults and larvae was considerably different, both in terms of the insecticides that were synergized (or antagonized for chlorfenapyr versus adults) and in terms of the degree of synergism. This result implies that the cytochrome P450s involved in metabolism of these insecticides are different between adults and larvae. Pyriproxyfen was confirmed as a potent IGR (EC50 of 0.0017 ng/ml) for mosquitoes, although tebufenozide lacked activity. The potential for use of these materials in mosquito control is discussed.

Selective accumulation of α-tocopherol in Drosophila is associated with cytochrome P 450 tocopherol-ω-hydroxylase activity but not α-tocopherol transfer protein

Humans and other mammals actively discriminate among the various forms of vitamin E to selectively retain α-tocopherol, but the phylogenetic breadth of this trait is unknown. We sought to determine if the fruit fly, Drosophila melanogaster, similarly discriminates and if so by what mechanism. Larvae and adult flies fed diets containing predominantly γ- and δ-tocopherols were enriched in α-tocopherol. Inclusion in the diet of piperonyl butoxide (PBO), an insect cytochrome P 450 inhibitor and inhibitor of tocopherol-ω-hydroxylase activity, greatly elevated tissue levels of δ-tocopherol but not α-tocopherol. Drosophila microsomes exhibited tocopherol-ω-hydroxylase activity in the order of δ-T > γ-T ≫ α-T, a pattern consistent with the effect of PBO in vivo. To determine if selectivity involved α-tocopherol transfer protein (α-TTP), adult flies were fed an equimolar mixture of d 3-RRR- and d 6-all-racemic α-tocopherol. Flies exhibited a d 3/ d 6 ratio of 1.03, demonstrating an inability to discriminate on the basis of phytyl tail stereochemistry, a hallmark of α-TTP activity. We conclude that Drosophila preferentially accumulates α-tocopherol via a mechanism involving cytochrome P 450 tocopherol-ω-hydroxylase-mediated catabolism of other tocopherols, but not a mammalian-like α-TTP. The selective pressure favoring this trait and its remarkable conservation from insects to humans requires elucidation.

Permethrin Resistance Mechanisms in the Beet Armyworm (Spodoptera exigua (Huebner))

The toxicity of pyrethroids was evaluated in a permethrin-susceptible (TS) and a permethrin-resistant (TR) strain of the beet armyworm, Spodoptera exigua (Hubner). The TR-strain showed 92-fold more resistance to permethrin and higher cross-resistance (97- and 130-fold, respectively) to cypermethrin and fenvalerate than the TS-strain. Moreover, all larval instars exhibited greater susceptibility to permethrin in the TS-strain than TR-strain. There was very little difference in susceptibility between the two strains with respect to chlorphenapyr. The effect of piperonyl butoxide on the toxicity of permethrin indicated that the resistance of the TR-strain is due to enhanced metabolic detoxification by cytochrome P450 monooxygenase. © Pesticide Science Society of Japan

Functional diversity of cytochrome P450s of the white-rot fungus Phanerochaete chrysosporium

The functional diversity of cytochrome P450s (P450s) of the white-rot basidiomycete, Phanerochaete chrysosporium, was studied. A series of compounds known to be P450 substrates of other organisms were utilized for metabolic studies of P. chrysosporium. Metabolic conversions of benzoic acid, camphor, 1,8-cineol, cinnamic acid, p-coumaric acid, coumarin, cumene, 1,12-dodecanediol, 1-dodecanol, 4-ethoxybenzoic acid, and 7-ethoxycoumarin were observed with P. chrysosporium for the first time. 1-Dodecanol was hydroxylated at seven different positions to form 1,12-, 1,11-, 1,10-, 1,9-, 1,8-, 1,7-, and 1,6-dodecandiols. The effect of piperonyl butoxide, a P450 inhibitor, on the fungal conversion of 1-dodecanol was also investigated, indicating that hydroxylation reactions of 1-dodecanol were inhibited by piperonyl butoxide in a concentration-dependent manner. With 11 substrates, 23 hydroxylation reactions and 2 deethylation reactions were determined and 6 products were new with the position of hydroxyl group incorporated. In conclusion, fungal P450s were shown to have diverse and unique functions.

Reproductive and neurobehavioural effects of piperonyl butoxide administered to mice in the diet

Piperonyl butoxide was given in the diet to mice to provide levels of 0 (control), 0.01, 0.03 and 0.09% from 5 weeks of age of the F0 generation to 9 weeks of age of the F1 generation, and selected reproductive and neurobehavioural parameters were measured. There were no adverse effects of piperonyl butoxide on either litter size, litter weight or sex ratio at birth. The average body weight of male offspring was significantly increased in the middle-dose group at post-natal days 4 and 7 during lactation. That of female offspring was significantly increased in the middle-dose group at post-natal days 7 and 14 during lactation. In behavioural developmental parameters, surface righting at post-natal day 7 was significantly delayed in the higher-dose groups in male offspring, and those effects were significantly dose related (p < 0.01). Olfactory orientation at post-natal day 14 was significantly depressed in the higher-dose groups in male offspring, and those effects were significantly dose related (p < 0.01). For movement activity of exploratory behaviour at 9 weeks of age of the F1 generation, the total distance of males was significantly increased in the higher-dose groups, and those effects showed a dose-related manner (p < 0.01). Average distance and speed were significantly increased in the high-dose group, and those effects showed a dose-related manner (p < 0.01 in each). The dose levels of piperonyl butoxide in the present study produced some adverse effects in reproductive and neurobehavioural parameters in mice.

Fenbendazole pharmacokinetics, metabolism, and potentiation in horses.

The present study was designed to describe the pharmacokinetics and fecal excretion of fenbendazole (FBZ) and fenbendazole sulphoxide (FBZSO) and their metabolites in horses, to investigate the effects which concurrent feeding has on the absorption and pharmacokinetics of FBZ, and to determine the effect of coadministration of the metabolic inhibitor piperonyl-butoxide on the in vivo pharmacokinetics and in vitro liver microsomal metabolism of sulfide and sulfoxide benzimidazoles. The effect of piperonyl-butoxide on the enantiomeric genesis of the sulfoxide moiety was also investigated. Following administration of FBZSO and FBZ, the fenbendazole sulphone metabolite predominated in plasma, and the C(max) and area under the plasma curve (AUC) values for each moiety were larger (P < 0.001) following FBZSO than FBZ. In feces the administered parent molecule predominated. The combined AUC for active benzimidazole moieties following oral administration of FBZ (10 mg/kg) in horses was almost 4 times as high in unfed horses (2.19 microg x h/ml) than in fed horses (0.59 microg x h/ml), and coadministration of piperonyl-butoxide significantly increased the AUC and C(max) of active moieties following intravenous administration of FBZSO and oral administration of FBZ. When FBZSO was administered i.v. as a racemate, the first enantiomer of oxfendazole (FBZSO-1) predominated in plasma, however, following coadministration with piperonyl-butoxide, the second enantiomer of oxfendazole (FBZSO-2) predominated for 10 h. Piperonyl-butoxide significantly reduced the oxidative metabolism of FBZSO and FBZ in equine liver microsomes and altered the ratio of enantiomers FBZSO-1/FBZSO-2 from >4:1 to 1:1. It is concluded that in horses efficacy of FBZSO and FBZ could be improved by administration to unfed animals and coadministration with piperonyl-butoxide.

Effect of piperonyl butoxide on diazinon resistance in field strains of the sheep blowfly, Lucilia cuprina (Diptera: Calliphoridae), in New Zealand

AbstractPretreatment of first instar larvae of 28 resistant strains of Lucilia cuprina(Wiedemann) with the inhibitor of microsomal oxidases, piperonyl butoxide, resulted in a biphasic response to the phosphorothioate insecticide diazinon. Analysis of the data revealed a complex response in which both synergist-dependent and independent effects occurred. The responses varied markedly from strain to strain. A laboratory susceptible strain and field strains with resistance factors of less than 20-fold exhibited, in the presence of piperonyl butoxide, an increased LC50 with respect to diazinon whereas those strains with &gt; 20-fold resistance were synergized by the compound. We conclude tentatively that microsomal mixed-function oxidases play a contributory role in the development of resistance and that the variation in synergist effect from strain to strain may be attributed, at least in part, to the two-fold effect of these enzymes on phosphorothioate insecticides such as diazinon.