Efficacy of pharmacokinetic interactions between piperonyl butoxide and albendazole against gastrointestinal nematodiasis in goats.

To test the hypothesis that modulation of hepatic microsomal sulphoxidation and sulphonation by the cytochrome P450 inhibitor piperonyl butoxide could increase bioavailability of albendazole, the present study was undertaken to understand the pharmacokinetics of albendazole in goats at a dose of 7.5 mg kg- 1 body weight with and without co-administration with piperonyl butoxide at 63.0 mg kg- 1 body weight. Plasma albendazole sulphoxide metabolite, the anthelmintically active moiety, reached its maximum concentration of 0.322 ± 0.045 µg ml- 1 and 0.384 ± 0.013 µg ml- 1 at 18 h and 24 h after administration of albendazole alone and co-administration of albendazole with piperonyl butoxide, respectively. Analysis of the data revealed statistically increased albendazole sulphoxide levels at 24 (P 0.05) in values of maximum concentration (normal and calculated) could be observed between groups of goats. However, values of time to reach the concentration maximum (normal and calculated), area under the concentration-time curve (0-∞ and calculated), minimum residence time, distribution half-life, elimination half-life and total area under the first movement of plasma drug concentration-time curve were significantly higher (P <  0.05) in plasma levels of albendazole sulphoxide in goats following single oral co-administration of albendazole with piperonyl butoxide. The faecal egg count reduction and lower 95% confidence limit for the group treated with albendazole alone were 97 and 68%, while for co-administration of albendazole and piperonyl butoxide the values were 99 and 97%, respectively. The ED50 for egg hatch was 0.196, indicating suspected resistance to benzimidazole anthelmintics. The drug combination proved efficacious against an albendazole-resistant nematode parasite population in goats.

Metabolism and excretion of piperonyl butoxide in the rat.

[14C]-piperonyl butoxide (PBO) was administered to male and female rats by gavage at a dose rate of 50 or 500 mg kg-1 body weight. In all cases, the radioactivity was rapidly excreted with 87-99% being found in the 0-48-h excreta and the majority of the dose (64.1-85.0%) being eliminated in faeces. The metabolism of PBO was complex with over 25 peaks of radioactivity being seen by radio-high-performance liquid chromatography (HPLC). Using HPLC/tandem mass spectrometry (MS/MS) and nuclear magnetic resonance (NMR), 12 urine metabolites were assigned structures together with four plus PBO in faeces. Metabolism occurred at two sites: the methylenedioxy ring, which opened to form a catechol that could then undergo methylation, and the 2-(2-butoxyethoxy)ethoxymethyl side-chain, which underwent sequential oxidation to a series of alcohols and acids. The identified metabolites accounted for approximately 60% of the administered dose.

Modelling the effects of alcohol ethoxylates on diffusion of pesticides in the cuticular wax of Chenopodium album leaves.

Cuticular waxes represent the first and, in most cases, the limiting barrier for foliar uptake of pesticides from solution. Sorption of pesticides in reconstituted cuticular wax (wax/water partition coefficients) of Chenopodium album L. and in isolated cuticular membranes (cuticle/water partition coefficients) of Prunus laurocerasus L. was determined. Diffusion coefficients of pesticides in reconstituted cuticular wax of C. album leaves were size-dependent, increasing with increasing molar volume. In the presence of alcohol ethoxylates, diffusion coefficients were enhanced by up to two orders of magnitude, and size selectivity was significantly decreased. The accelerating effect and the decrease in size selectivity were attributed to plasticisation of the cuticular wax by the alcohol ethoxylates increasing the fluidity in the wax. A free volume model adopted from polymer science was successfully applied to predict diffusion coefficients of pesticides on the basis of the transport properties of the wax (size selectivity and crystallinity), the molar volume of the diffusing compound and the accelerator concentration in the wax.

Biotransformation and bioconcentration of pyrene in Daphnia magna.

Water fleas (Daphnia magna) were exposed to [14C]pyrene in the presence and absence of piperonyl butoxide (PBO), a general cytochrome P450 (CYP) inhibitor, in organic carbon-free artificial freshwater (AFW, DOC<0.2 mg l(-1)) and in natural lake water (DOC=19.9 mg l(-1)) for 24 h. The bioconcentration of total radioactivity after 24 h exposure was 50% lower in the natural lake water, indicating decreased bioavailability of pyrene by the dissolved organic matter. However, the proportions of parent compound were only ca. 12 and 19% of the total body burden in daphnids exposed in AFW and natural lake water, respectively. Therefore, the tissue concentration of the parent pyrene was not significantly different in the daphnids exposed in the two different waters. Due to extensive biotransformation the bioconcentration factor (BCF) of parent pyrene was only 16 and 23% of the BCF calculated on the basis of total radioactivity in the daphnids in AFW and natural lake water, respectively. The proportion of parent pyrene was significantly higher (over 60%) in the daphnids exposed simultaneously to PBO, which indicates the involvement of CYP monooxygenases in the biotransformation. Furthermore, increasing PBO concentration decreased the accumulation of total radioactivity in AFW but not in the natural lake water. The data demonstrate capability and importance of CYP monooxygenases in biotransformation of polycyclic aromatic hydrocarbons in D. magna.

Plasma achiral and chiral pharmacokinetic behaviour of intravenous oxfendazole co-administered with piperonyl butoxide in sheep.

Co-administration of piperonyl butoxide (PB) potentiates fenbendazole (FBZ) in small ruminants. The resultant increase in bioavailability of FBZ and its metabolite oxfendazole (OFZ) has important implications for the efficacy of these drugs against benzimidazole (BZD)-resistant strains of Teladorsagia circumcincta. This study evaluated the racemic (achiral) and enantiomeric (chiral) plasma disposition kinetics of OFZ and its metabolites after the co-administration of PB and OFZ in sheep. Six 6-8-month-old, parasite-free, female Dorset sheep (30-40 kg) were used in a two-phase crossover experiment. In phase I, three sheep received 30 mg/kg PB orally, followed by a single intravenous (i.v.) injection of OFZ at 5 mg/kg. The other three animals were treated similarly except that 5 mL of water replaced PB. In phase 2, treatments for the two groups were reversed and were given 14 days after the initiation of phase I. Three analytes OFZ, FBZ and fenbendazole sulphone (FBZSO(2)) were recovered in plasma up to 48 h post-treatment in both experimental groups. Achiral and chiral pharmacokinetic (PK) profiles for OFZ, after the co-administration of PB, were characterized by a significantly greater area under the concentration--time curve (AUC) and a longer mean residence time (MRT). Chiral OFZ distribution ratios were comparable in both treatment groups. Piperonyl butoxide treatment markedly influenced the plasma PK profiles for FBZ and FBZSO(2) following OFZ administration. Production of FBZ was enhanced as reflected by increased (> 60%) AUC, delayed T(max) and a significantly delayed (> 45%) elimination (t(1/2)(el)). Although AUC values for FBZSO(2) were not significantly different between groups, this metabolite was depleted more slowly from plasma (t(1/2)(el) > 60% and MRT > 42%) following PB treatment. This study demonstrated that PB co-administration is associated with an inhibition of OFZ biotransformation, as evidenced by the significantly higher plasma concentrations of OFZ and FBZ, and this could have important implications in terms of anti-parasite therapy against BZD-resistant parasite strains.

Thiols and polyamines in the potentiation of malathion toxicity in larval stages of the toad Bufo arenarum.

Treatment with exogenous spermidine enhanced acute malathion toxicity during larval development of the toad Bufo arenarum Hensel. The polyamine was rapidly incorporated in the larvae with a subsequent metabolization to putrescine and spermine, which were excreted to the media. Endogenous polyamine levels were not changed by either spermidine or malathion treatments. However, 0.5-mM spermidine modified malathion uptake and bioavailability increasing the concentration of the xenobiotic in the larvae. The amount of reduced thiols was decreased by both compounds, but the depletion was insufficient to induce cytotoxicity. The oxidative degradation of polyamines competes for the pool of reduced glutathione used in the conjugation of malathion in the larvae, thus leading to the reported potentiation of toxicity. Our results suggest that exposure to thiols-depleting agents may induce alteration of organophosphate degradation in amphibian larvae.

Pharmacokinetic mechanisms associated with synergism by DEF of cypermethrin toxicity in larval and adult Helicoverpa zea, Spodoptera frugiperda, and Agrotis ipsilon (Lepidoptera: Noctuidae).

Penetration, metabolism, and excretion of radiocarbon were observed after topical treatment of Helicoverpa zea (Boddie), Spodoptera frugiperda (J. E. Smith), and Agrotis ipsilon (Hufnagle) larvae and adults with cypermethrin-14C. These pharmacokinetic events usually were higher with trans-cypermethrin-14C than with cis-cypermethrin-14C. They also were generally higher with H. zea and S. frugiperda than with A. ipsilon, and they were higher in larvae than in adults. No marked sex differences in the degradation of trans-cypermethrin were apparent. Pretreatment of H. zea, S. frugiperda, and A. ipsilon larvae and adults with S,S,S-tri-n-butyl phosphorotrithioate (DEF) 30 min before application of cypermethrin resulted in a perturbation of trans-cypermethrin pharmacokinetics manifested primarily by a lower rate of pyrethroid metabolism as compared with that in the absence of DEF. Appreciably higher internal levels of the toxic parent pyrethroid were often observed in the presence of DEF than in the absence of DEF in most cases. Suppression of cypermethrin penetration and elimination also was usually detected. Inhibition by DEF of the enzymatic degradation of cypermethrin may account for the synergy observed between these two compounds.

Effects of temperature and concentration of the accelerators ethoxylated alcohols, diethyl suberate and tributyl phosphate on the mobility of [14C]2,4-dichlorophenoxy butyric acid in plant cuticles.

Intrinsic activities of monodisperse ethoxylated dodecanols (MEDs), diethyl suberate (DESU) and tributyl phosphate (TBP) were investigated using Stephanotis floribunda leaf cuticular membranes (CMs) and [14C]2,4-dichlorophenoxy butyric acid (2,4-DB) as a model solute. When sorbed in cuticular membranes, MEDs, DESU and TBP increase solute mobility and are called accelerators for this reason. With MEDs, dose-effect curves (log mobility vs accelerator concentration) were linear but, with DESU and TBP, curves convex to the x axes were obtained that approached a maximum at 90 and 150 g kg-1, respectively. Accelerators increased the mobility of 2,4-DB in the CMs by 9- to 48-fold, and effects were larger at lower temperatures (range 15-30 degrees C). Activation energy for diffusion of 2,4-DB was 105 kJ mol-1, decreasing with increasing accelerator concentrations to 26 kJ mol-1 with DESU at 90 g kg-1 and 64 kJ mol-1 with TBP at 150 g kg-1. Thus, the intrinsic activity of DESU was much higher than that of TBP, which implies that, for a given effect, less DESU than TBP would be needed. MEDs were also very effective accelerators, lowering activation energies to 36 kJ mol-1. Data are discussed in relation to increasing rates of foliar penetration of active ingredients at low temperatures.

Absorption and mass balance of piperonyl butoxide following an 8-h dermal exposure in human volunteers.

Dermal absorption, metabolism and excretion of piperonyl butoxide (PBO) was studied using 14C-PBO either by itself as a 3% (w/w) solution in isopropyl alcohol or as a 4% (w/w) solution in an aqueous end-use formulation. Each of these two formulations were tested on four young, healthy male volunteers, using a single topical application on the ventral forearm under non-occlusive conditions for an 8-h period. The application sites were thoroughly cleaned with cotton swabs moistened with isopropyl alcohol, then rinsed with isopropyl alcohol. Blood from the ipsilateral and contralateral arms, urine and feces were collected at selected intervals during the 8-h application and through a 120-h post-application period. The application area was also tape-stripped to determine if any of the test material accumulated in the stratum corneum. These samples provided data which permitted insight into the kinetics of penetration and elimination processes of PBO. The absorption of PBO either by itself or formulated was very poor, as demonstrated by the radioactivity excreted in the urine, and radioactivity in the ipsilateral plasma. When dosed by itself, approximately 1.78% of the dose was excreted in the urine. In contrast, only 0.47% of the formulated PBO was excreted in the urine. Trace radioactivity was detected in the feces from both formulations. The absorbed radioactivity was rapidly eliminated in the urine. There was no evidence of accumulation of PBO in the skin as evidenced by low amounts of radioactivity in the tape-strippings. The majority of the applied radioactivity was recovered from the skin surface. Total recovery of the applied radioactivity was 100.86 and 104.22% for PBO and the formulated product respectively. Absorbed PBO was completely metabolized to at least three major metabolites prior to its excretion in the urine. The three metabolites represented over 70% of the excreted radioactivity for PBO. The HPLC retention times for these metabolites are different than that seen in rats. The structures of these metabolites have not been elucidated.

Testicular toxicity of molinate in the rat: metabolic activation via sulfoxidation.

Molinate is a thiocarbamate herbicide widely used in rice culture. Studies conducted for regulatory purposes have indicated that molinate exposure causes male reproductive damage in rats. The present study describes the testicular lesion after administration of single doses of molinate. The hypothesis that a metabolite of molinate is responsible for testicular toxicity was also investigated. Testicular damage was evaluated histopathologically in Sprague-Dawley rats 48 h and 1, 2, and 3 weeks after administration of molinate (100-400 mg/kg i.p.). No testicular damage was seen at any time point at the 100 mg/kg dose level. Damage was first seen 1 week after 200 mg/kg and 48 h after 400 mg/kg. The lesion was characterized by Sertoli cell vacuolation, failed spermiation, and phagocytosis of spermatids particularly evident at Stages X and XI. With increasing time, damage progressed until disorganization of the seminiferous epithelium was extensive, multinucleated giant cells were numerous, and neither spermatozoa nor late step spermatids were present. At 3 weeks after administration of the two higher-dose levels, germ cells in the seminiferous tubules were almost completely absent. Administration of the sulfoxide metabolite of molinate (200 mg/kg i.p.) caused testicular damage similar in severity to that seen at the 400 mg/kg dose level for the parent compound, indicating that it was more potent as a testicular toxicant. In vitro metabolism studies using liver and testis microsomes found that the major metabolite in both preparations was molinate sulfoxide. Testis microsomes produced only slightly less sulfoxide when compared with liver microsomes. Molinate was also metabolized via ring hydroxylation to form small amounts of hydroxymolinate. The amount of hydroxymolinate was substantially less in testis microsomes. Overall, these data indicate that sulfoxidation of molinate plays a role in molinat-induced testicular toxicity. Moreover, molinate is metabolized readily by both liver and testis microsomal enzymes, suggesting that the molinate toxic metabolite could be formed in the testis in close proximity to its site of action.