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11.
Ballent M Lifschitz A Virkel G Sallovitz J Maté L Lanusse C 《Veterinary journal (London, England : 1997)》2012,192(3):422-427
The impact of an efflux pump-related interaction between ivermectin and danofloxacin on their intestinal transport (ex vivo) and disposition kinetics (in vivo) was assessed. Eighteen male Corriedale sheep were randomly assigned to one of three groups. Animals in Group A received 0.2mg/kg ivermectin by SC injection, those in Group B were given 6 mg/kg danofloxacin SC on two occasions 48 h apart and those in Group C were treated with both compounds at the same rates. Plasma concentrations of ivermectin and danofloxacin were measured by HPLC using fluorescence detection. Ex vivo intestinal drug transport activity was measured by the use of the Ussing chamber technique. Plasma concentrations of ivermectin in the first 6 days after injection tended to be higher in Group C than Group A. Contemporaneous treatment with ivermectin significantly increased systemic exposure to danofloxacin (AUC values were 32-35% higher) and prolonged the elimination half-life of danofloxacin (40-52% longer). Ex vivo, incubation with ivermectin significantly decreased the efflux transport of rhodamine 123, a P-glycoprotein substrate, in sheep intestine, but no significant effect of danofloxacin on transport activity was observed. Evaluation of the interaction of danofloxacin with the breast cancer resistance protein (BCRP) showed that pantoprazole and ivermectin significantly decreased danofloxacin secretion in the rat intestine. Thus, the ivermectin-induced reduction of danofloxacin efflux transport observed in this study may involve BCRP activity but the involvement of P-glycoprotein cannot be ruled out. 相似文献
12.
M. Ballent M. R. Wilkens L. Maté A. S. Muscher G. Virkel J. Sallovitz B. Schröder C. Lanusse A. Lifschitz 《Journal of veterinary pharmacology and therapeutics》2013,36(6):576-582
The role of the transporter P‐glycoprotein (P‐gp) in the disposition kinetics of different drugs therapeutically used in veterinary medicine has been demonstrated. Considering the anatomo‐physiological features of the ruminant species, the constitutive expression of P‐gp (ABCB1) along the sheep gastrointestinal tract was studied. Additionally, the effect of repeated dexamethasone (DEX) administrations on the ABCB1 gene expression in the liver and small intestine was also assessed. The ABCB1 mRNA expression was determined by real‐time quantitative PCR. P‐gp activity was evaluated in diffusion chambers to determine the efflux of rhodamine 123 (Rho 123) in the ileum from experimental sheep. The constitutive ABCB1 expression was 65‐fold higher in the liver than in the intestine (ileum). The highest ABCB1 mRNA expression along the small intestine was observed in the ileum (between 6‐ and 120‐fold higher). The treatment with DEX did not elicit a significant effect on the P‐gp gene expression levels in any of the investigated gastrointestinal tissues. Consistently, no significant differences were observed in the intestinal secretion of Rho 123, between untreated control (Peff S‐M = 3.99 × 10?6 ± 2.07 × 10?6) and DEX‐treated animals (Peff S‐M = 6.00 × 10?6 ± 2.5 × 10?6). The understanding of the efflux transporters expression and activity along the digestive tract may help to elucidate clinical implications emerging from drug interactions in livestock. 相似文献
13.
Mariana Ballent Maria Laura Mat Paula Dominguez Guillermo Virkel Melanie Albrich Anne Lespine Carlos Lanusse Adrian Luis Lifschitz 《Journal of veterinary pharmacology and therapeutics》2019,42(2):189-196
The aim of the current study was to evaluate the in vivo pharmacokinetic of ivermectin (IVM) after the administration of a long‐acting (LA) formulation to sheep and its impact on potential drug‐drug interactions. The work included the evaluation of the comparative plasma profiles of IVM administered at a single therapeutic dose (200 μg/kg) and as LA formulation at 630 μg/kg. Additionally, IVM was measured in different gastrointestinal tissues at 15 days posttreatment with both IVM formulations. The impact of the long‐lasting and enhanced IVM exposure on the disposition kinetics of abamectin (ABM) was also assessed. Plasma (IVM and ABM) and gastrointestinal (IVM) concentrations were analyzed by HPLC with fluorescent detection. In plasma, the calculated Cmax and AUC0‐t values of the IVM‐LA formulation were 1.47‐ and 3.35‐fold higher compared with IVM 1% formulation, respectively. The T1/2ab and Tmax collected after administration of the LA formulation were 2‐ and 3.5‐fold longer than those observed after administration of IVM 1% formulation, respectively. Significantly higher IVM concentrations were measured in the intestine mucosal tissues and luminal contents with the LA formulation, and in the liver, the increase was 7‐fold higher than conventional formulation. There was no drug interaction between IVM and ABM after the single administration of ABM at 15 days post‐administration of the IVM LA formulation. The characterization of the kinetic behavior of the LA formulation to sheep and its potential influence on drug‐drug interactions is a further contribution to the field. 相似文献
14.
Lifschitz Virkel Imperiale Sutra Galtier Lanusse & Alvinerie 《Journal of veterinary pharmacology and therapeutics》1999,22(4):266-273
The time of parasite exposure to active drug concentrations determines the persistence of the antiparasitic activity of endectocide compounds. This study evaluates the disposition kinetics of moxidectin (MXD) in plasma and in different target tissues following its subcutaneous (s.c.) administration to cattle. Eighteen male, 10-month old Holstein calves weighing 120-140 kg were subcutaneously injected in the shoulder area with a commercially available formulation of MXD (Cydectin 1%, American Cyanamid, Wayne, NJ, USA) at 200 micrograms/kg. Two treated calves were killed at each of the following times post-treatment: 1, 4, 8, 18, 28, 38, 48, 58 and 68 days. Abomasal and small intestine mucosal tissue and fluids, bile, faeces, lung, skin and plasma samples were collected, extracted, derivatized and analysed to determine MXD concentrations by high performance liquid chromatography (HPLC) with fluorescence detection. MXD was extensively distributed to all tissues and fluids analysed, being detected (concentrations > 0.1 ng/g; ng/mL) between 1 and 58 days post-treatment. MXD peak concentrations were attained during the first sampling day. MXD maximum concentration (Cmax) values ranged from 52.9 (intestinal mucosa) up to 149 ng/g (faeces). The mean residence time (MRT) in the different tissues and fluids ranged from 6.8 (abomasal mucosa) up to 11.3 (bile) days. MXD concentrations in abomasal and intestinal mucosal tissue were higher than those detected in plasma; however, there was a high correlation between MXD concentrations observed in plasma and those detected in both gastrointestinal mucosal tissues. MXD concentrations were markedly greater in the mucosa than in its respective digestive fluid (P < 0.01). MXD concentrations in skin were higher than those found in plasma (P < 0.01). Drug concentrations recovered in the dermis were greater than those detected in the hypodermal tissue (P < 0.05). Large concentrations of MXD were excreted in bile and faeces. These findings may contribute to an understanding of the relationship between the kinetic behaviour and the persistence of the antiparasite activity of MXD against different ecto-endoparasites in cattle. 相似文献
15.
Solana H Scarcella S Virkel G Ceriani C Rodríguez J Lanusse C 《Veterinary research communications》2009,33(2):163-173
Fascioliasis causes important economic losses in ruminant species all over the world. Its control is largely based on the
use of the flukicidal compound triclabendazole (TCBZ). However, its chemically related benzimidazole anthelmintic albendazole
(ABZ) is being successfully used to control TCBZ-resistance flukes. This research gains some insights into the comparative
molecular behaviour of both anthelmintics within the target fluke. The goals of the current work were: (i) to assess the competitive
binding of ABZ and TCBZ to cytosolic proteins of F. hepatica, and (ii) to evaluate the enantioselective biotransformation of ABZ in microsomal fractions obtained from TCBZ-susceptible
and TCBZ-resistant strains of the liver fluke. Cytosolic proteins from fluke specimens bound TCBZ with greater affinity (83%)
than ABZ (44%) and the fraction of TCBZ bound to cytosolic proteins was not displaced by ABZ. The microsomes from both -susceptible
and resistant flukes sulphoxidized ABZ into ABZ sulphoxide (ABZSO). However, this oxidative activity was 49% higher in microsomes
from TCBZ-resistant flukes (P < 0.001) with a predominant production of the (+) ABZSO enantiomer. As earlier shown for TCBZ,
the results reported here confirm an enhanced ability for ABZ oxidation in TCBZ-resistant flukes. While this enhanced oxidative
metabolism of ABZ may cooperate to the resistance phenomenon, other pharmacodynamic-based mechanisms may be involved, which
would explain why, although being chemically-related, ABZ remains efficacious against TCBZ resistant flukes under field conditions. 相似文献
16.
Comparison of pharmacokinetic variables for two injectable formulations of netobimin administered to calves 总被引：1，自引：0，他引：1
In a 4 x 4 crossover-design study, pharmacokinetic variables of 2 injectable formulations of netobimin (trisamine salt solution and zwitterion suspension) were compared after SC administration in calves at dosage of 12.5 mg/kg of body weight. Netobimin parent drug was rapidly absorbed, being detected between 0.25 and 12 hours after treatment, with maximal plasma drug concentration (Cmax) values of 2.20 +/- 1.03 micrograms/ml achieved at 0.75 +/- 0.19 hour (trisamine) and 1.37 +/- 0.59 micrograms/ml at 0.81 +/- 0.18 hour (zwitterion). Netobimin area under the plasma concentration-time curve (AUC) was 7.59 +/- 3.11 micrograms.h/ml (trisamine) and 6.98 +/- 1.60 micrograms.h/ml (zwitterion). Elimination half-life (t1/2 beta) was 2.59 +/- 0.63 hours (trisamine) and 3.57 +/- 1.45 hours (zwitterion). Albendazole was not detected at any time. Albendazole sulfoxide was detected from 4 hours up to 20 hours (trisamine) and from 6 hours up to 24 hours (zwitterion) after administration of the drug. The Cmax values were 0.48 +/- 0.16 micrograms/ml and 0.46 +/- 0.26 micrograms/ml for trisamine and zwitterion formulations, respectively, achieved at time to peak drug concentration (Tmax) values of 9.50 +/- 1.41 hours (trisamine) and 11.30 +/- 1.04 hours (zwitterion). Albendazole sulfoxide AUC was 3.86 +/- 1.04 micrograms.h/ml (trisamine) and 4.40 +/- 3.24 micrograms.h/ml (zwitterion); t1/2 beta was 3.05 +/- 0.75 hours (trisamine) and 3.90 +/- 1.44 hours (zwitterion). Albendazole sulfone was detected from 4 (trisamine) or 6 hours (zwitterion) to 24 hours after treatment.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
17.
Karen E. Larsen Adrin L. Lifschitz Carlos E. Lanusse Guillermo L. Virkel 《Journal of veterinary pharmacology and therapeutics》2019,42(5):548-555
The combination of the organophosphate (OP) chlorpyrifos (CPF) and the pyrethroid cypermethrin (CPM) is commonly marketed as pour‐on formulations for the control of sheep lice, ked, and blowflies. CPF irreversibly inhibits acetylcholinesterases (AChE), while pyrethroids are not AChE inhibitors. However, combinations of pyrethroids with OPs showed a highly synergistic effect on AChE inhibition. Thus, the aim of the current work was to evaluate in vitro and in vivo the inhibitory potency of both pesticides, alone and in combination with AChE and butyrylcholinesterase (BChE) activities in sheep blood. In vitro, IC50 values were similar after CPF or CPF plus CPM incubations. The pour‐on coadministration of recommended doses of CPF and CPM did not cause a significant inhibition of AChE and BChE in sheep blood. Only slight percentages of inhibition of their catalytic activities were observed when both drugs were given at 4‐fold higher dose rates. The lower systemic availability of topical administration of OPs in sheep may help to explain the lower degree of inhibition of blood AChE and BChE in vivo. The results emerged from this research are a further contribution to the knowledge of the risks of implementing higher dosage regimens of OPs‐containing antiparasitic formulations. 相似文献
18.
Assessment of the pharmacological interactions between the nematodicidal fenbendazole and the flukicidal triclabendazole: In vitro studies with bovine liver microsomes and slices 
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下载免费PDF全文 P. Viviani A. L. Lifschitz M. L. Maté J. P. García C. E. Lanusse G. L. Virkel 《Journal of veterinary pharmacology and therapeutics》2018,41(3):476-484
Parasitic diseases have a significant impact on livestock production. Nematodicidal drugs, such as fenbendazole (FBZ) or its oxidized metabolite oxfendazole (OFZ), can be used along with the trematodicidal triclabendazole (TCBZ), to broaden the spectrum of anthelmintic activity. However, co‐exposure to these compounds could lead to drug–drug (D‐D) interactions and eventually alter the clinical profile of each active principle. The aim of this study was to assess the presence of such interactions by means of two in vitro models, namely bovine liver microsomal fractions and bovine precision‐cut liver slices (PCLSs). To this end, an in vitro assessment involving incubation of FBZ and TCBZ or a combination of FBZ and TCBZ was carried out. Results with microsomal fractions showed a 78.4% reduction (p = .002) in the rate of OFZ production upon co‐incubation, whereas the sulfoxide metabolite of TCBZ (TCBZSO) exhibited a decreasing tendency. With PCLS, OFZ accumulation in the incubation medium increased 1.8‐fold upon co‐incubation, whereas TCBZSO accumulation decreased by 28%. The accumulation of FBZ and OFZ in the liver tissue increased upon 2‐hr co‐incubation, from 2.1 ± 1.5 to 18.2 ± 6.1 (p = .0009) and from 0.4 ± 0.1 to 1.3 ± 0.3 nmol (p = .0005), respectively. These results confirm the presence of D‐D interactions between FBZ and TCBZ. Further studies are needed to determine the extent of involvement of drug‐metabolizing enzymes and membrane transporters in interactions between compounds largely used in livestock production systems. 相似文献
19.
Virkel G Lifschitz A Sallovitz J Pis A Lanusse C 《Journal of veterinary pharmacology and therapeutics》2006,29(3):213-223
Triclabendazole (TCBZ) is an halogenated benzimidazole (BZD) compound worldwide used to control immature and adult stages of the liver fluke Fasciola hepatica. The purpose of this investigation was to characterize in vitro the patterns of hepatic and ruminal biotransformation of TCBZ and its metabolites in sheep. TCBZ parent drug was metabolized into its sulphoxide (TCBZSO), sulphone (TCBZSO2) and hydroxy derivatives by sheep liver microsomes. The same microsomal fraction was also able to oxidize TCBZSO into TCBZSO2 and hydroxy-TCBZSO (HO-TCBZSO). TCBZ sulphoxidation was significantly (P < 0.001) inhibited after inactivation of the flavin-monooxygenase (FMO) system (77% inhibition) as well as in the presence of the FMO substrate methimazole (MTZ) (71% inhibition). TCBZ sulphoxidative metabolism was also reduced (24% inhibition, P < 0.05) by the cytochrome P450 inhibitor piperonyl butoxide (PB). The rate of TCBZSO conversion into TCBZSO2 was also significantly inhibited by PB (55% inhibition), MTZ (52% inhibition) and also following FMO inactivation (58% inhibition). The data reported here indicate that the FMO is the main enzymatic pathway involved in TCBZ sulphoxidation (ratio FMO/P450 = 3.83 +/- 1.63), although both enzymatic systems participate in a similar proportion in the sulphonation of TCBZSO to form the sulphone metabolite (ratio FMO/P450 = 1.31 +/- 0.23). Additionally, ketoconazole (KTZ) did not affect TCBZ sulphoxidation but decreased (66% inhibition, P < 0.05) the formation of TCBZSO2. Similarly, inhibition of TCBZSO2 production was observed after incubation of TCBZSO in the presence of KTZ and erythromycin (ETM). Conversely, thiabendazole (TBZ) and fenbendazole (FBZ) did not affect the oxidative metabolism of both incubated substrates. The sheep ruminal microflora was able to reduce the sulphoxide (TCBZSO) into the parent thioether (TCBZ). The ruminal sulphoreduction of the HO-TCBZSO derivative into HO-TCBZ was also demonstrated. The rate of sulphoreduction of HO-TCBZSO was significantly (P < 0.05) higher than that observed for TCBZSO. The metabolic approach tested here contributes to the identification of the different pathways involved in drug biotransformation in ruminant species. These findings on the pattern of hepatic and ruminal biotransformation of TCBZ and its main metabolites are a further contribution to the understanding of the pharmacological properties of widely used anthelmintics in ruminants. Comprehension of TCBZ metabolism is critical to optimize its flukicidal activity. 相似文献
20.
Alvinerie M Sutra JF Galtier P Lifschitz A Virkel G Sallovitz J Lanusse C 《Research in veterinary science》1999,66(1):57-61
Six calves (weight 210 to 230 kg) were dosed with an intra-ruminal slow-release bolus prepared to deliver ivermectin at a low daily dosage for 135 days. Ivermectin concentrations in jugular blood 160 days post-treatment were determined by high performance liquid chromatography (HPLC) using fluorescence detection. Ivermectin plasma concentrations increased gradually to achieve the steady-state concentration (20 ng ml(-1)) at approximately four days post-treatment, which was maintained for 120 days. The ivermectin peak plasma concentration (28.5 ng ml(-1)) was attained at 15 days post-administration of the bolus. The faecal ivermectin concentration rose to a maximal concentration of 4.1 microg g(-1) at four days post-treatment, dropping to a steady-state concentration of around 1.18 microg g(-1) which was maintained up to 120 days post-treatment. Ivermectin was detected in both plasma (0.05 ng ml(-1)) and faeces (2.67 ng g(-1)) up to 160 days. The high levels of ivermectin recovered in faeces indicate that a large proportion of the dose released by the bolus (80 to 90 per cent) is excreted in faeces. 相似文献