Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to th... more Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to the involvement of P-glycoprotein (P-gp) and cytochrome P450 3A in the metabolism of moxidectin, we studied the influence of various P-gp interfering agents (ivermectin, quercetin and ketoconazole) on the metabolism of 14C moxidectin in cultured rat hepatocytes over 72 h. This in vitro study allowed selection of compounds which are able to increase the moxidectin bioavailability in lambs. From this, the modulation of moxidectin pharmacokinetics in plasma of lambs was studied after co-administration of 0.2 mg kg(-1) moxidectin (subcutaneously (SC)) and 0.2 mg kg(-1) ivermectin (SC), or 10 mg kg(-1) quercetin (SC), or 10 mg kg(-1) ketoconazole (orally). Ivermectin and quercetin increased significantly the quantity of 14C moxidectin in the rat hepatocytes. Ketoconazole co-administration led to a higher concentration of moxidectin in the rat hepatocytes. In vivo, only quercetin was able to modify the pharmacokinetics of moxidectin in plasma of lambs by increasing significantly the area under the plasma concentration-time curve. This study allowed the use of a natural agent, quercetin, to improve the bioavailability of moxidectin.
Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to th... more Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to the involvement of P-glycoprotein (P-gp) and cytochrome P450 3A in the metabolism of moxidectin, we studied the influence of various P-gp interfering agents (ivermectin, quercetin and ketoconazole) on the metabolism of 14C moxidectin in cultured rat hepatocytes over 72 h. This in vitro study allowed selection of compounds which are able to increase the moxidectin bioavailability in lambs. From this, the modulation of moxidectin pharmacokinetics in plasma of lambs was studied after co-administration of 0.2 mg kg(-1) moxidectin (subcutaneously (SC)) and 0.2 mg kg(-1) ivermectin (SC), or 10 mg kg(-1) quercetin (SC), or 10 mg kg(-1) ketoconazole (orally). Ivermectin and quercetin increased significantly the quantity of 14C moxidectin in the rat hepatocytes. Ketoconazole co-administration led to a higher concentration of moxidectin in the rat hepatocytes. In vivo, only quercetin was able to modify the pharmacokinetics of moxidectin in plasma of lambs by increasing significantly the area under the plasma concentration-time curve. This study allowed the use of a natural agent, quercetin, to improve the bioavailability of moxidectin.
The parasiticide ivermectin and the antifungal drug ketoconazole are drugs that interact with P-g... more The parasiticide ivermectin and the antifungal drug ketoconazole are drugs that interact with P-glycoprotein. We have tested the ability of ketoconazole at a clinical dose to modify the pharmacokinetics of ivermectin in sheep. Lacaune lambs were administered with a single oral dose of ivermectin alone at 0.2 mg/kg (n = 5) or in combination with a daily oral dose of ketoconazole (10 mg/kg) given for 3 days before and 2 days after the ivermectin (n = 5). The plasma kinetics of ivermectin and its metabolite were followed over 15 days by HPLC analysis. Co-administration of ketoconazole induced higher plasma concentrations of ivermectin, leading to a substantial increase in the overall exposure of the animals to the drug. Ketoconazole did not reduce the production of the main ivermectin metabolite but it may rather act by inhibiting P-glycoprotein, and thus increasing the absorption of ivermectin. The use of a P-gp reversing agent such as ketoconazole could be useful tool to optimize antiparasitic therapy in the face of the worldwide development of anthelmintic resistance.
The cytochrome P450 (P450) superfamily represents a group of relevant enzymes in the field of dru... more The cytochrome P450 (P450) superfamily represents a group of relevant enzymes in the field of drug metabolism and several exogenous or constitutional factors contribute to regulate its expression. Cattle represent an important source of animal-derived food-products and studies concerning the P450 expression are needed for the extrapolation of pharmacotoxicological data from one species to another and for the evaluation of the consumer's risk associated with the consumption of harmful residues found in foodstuffs. In the present study, possible breed-, genderand species-differences in P4503A (the P450 subfamily more expressed in the human liver) expression were studied in vitro in Piedmontese (PDM) and Limousin (LIM) meat cattle breeds of both sexes and in domestic Ruminants (cattle, sheep and goats). Cytochrome P450 and P4503A contents as well as CYP3A-dependent drug metabolising enzymes (DME) were measured in liver microsomes. Significant lower levels of P450 (P < 0.001) and P4503A (P < 0.05) contents were observed in PDM vs. LIM of both sexes; the P4503A-dependent DME activities were significantly (P values ranging from 0.05 up to 0.001) higher in PDM cattle, particularly in males. A gendereffect in DME activities was noticed (P < 0.05) only in PDM male cattle. With regards to the species, the expression of both P4503A apoprotein and some of the related DME activities were more pronounced in sheep (P < 0.01 vs. cattle) and in goats (P < 0.05 vs. sheep; P < 0.01 vs. cattle) than in cattle. The significant differences in P4503A expression observed in LIM and PDM cattle are consistent with previously published data on strain-and breed-differences pointed out in rats and men. As far as a possible sex-effect is concerned, no clear-cut evidence is likely to be drawn. Finally, P4503A expression was more relevant in small ruminants. ruminants / liver drug metabolism / CYP3A / gender / breed
Some pharmacokinetic parameters of selamectin were determined in male (n = 5) and female (n = 5) ... more Some pharmacokinetic parameters of selamectin were determined in male (n = 5) and female (n = 5) Beagle dogs following a topical application at a dose rate of 6 mg/kg. The plasma concentration versus time data for the drug were analysed using a one-compartment model. The maximum plasma concentrations of 12.72+5.13 ng/ml for males and 22.65+11.95 ng/ml for females occurred around 5 days after administration. The area under the concentration^time curve (AUC) was 192.08+63.85 ng.day/ml for males and 370.97+146.87 ng.day/ml for females. The mean residence time was the same in males and females (12.55 days). This study reveals a sex-in£uence on the disposition of selamectin in the plasma of dogs, which implies that further information will be needed for correlation with e¤cacy studies in dogs.
The plasma kinetics disposition of moxidectin following a subcutaneous administration with a long... more The plasma kinetics disposition of moxidectin following a subcutaneous administration with a long-acting formulation (Cydectin 1 10%, Fort Dodge Animal Health, France) at the recommended dose of 1 mg kg À1 body weight was evaluated in Charolais cattle breed (five females weighing 425-450 kg) for 120 days. Furthermore, its concentration was measured in hair for the same period. After plasma extraction and derivatization, samples were analysed by HPLC with fluorescence detection. Moxidectin was first detected at 1 h after treatment for plasma (2.00 AE 1.52 ng ml À1) and at 2 days for hair (446.44 AE 193.26 ng g À1). The peak plasma concentration (C max) was 55.71 AE 15.59 ng ml À1 and 444.44 AE 190.45 ng g À1 for plasma and hair, respectively. The mean calculated time of peak occurrence (T max) was 3.40 AE 3.36 and 2 days for plasma and hair, respectively. The mean residence time (MRT) was 28.93 AE 2.87 and 13.32 AE 2.48 days for plasma and hair cattle. The area under concentration-time curve (AUC) was 1278.95 AE 228.92 ng day ml À1 and 2663.82 AE 1096.62 ng day g À1 for plasma and hair, respectively. At the last sampling time (120 days), the concentration was 1.91 AE 0.26 ng ml À1 and 0.69 AE 0.52 ng g À1 for plasma and hair, respectively. The bioavailability of this long-acting formulation of moxidectin is similar to that registered after subcutaneous administration of moxidectin in cattle at 0.2 mg kg À1 body weight. For the first time the moxidectin pharmacokinetics parameters in hair after a subcutaneous administration was described. The moxidectin profile concentrations in hair reflected that registered in plasma. The previous studies of efficacy have to be correlated to the extended period of absorption and distribution by the LA formulation due to the fivefold higher dose rate in comparison with the 1% injectable formulation (0.2 mg kg À1 body weight).
The pharmacokinetics and mammary excretion of moxidectin and eprinomectin were determined in wate... more The pharmacokinetics and mammary excretion of moxidectin and eprinomectin were determined in water buffaloes (Bubalus bubalis) following topical administration of 0.5 mg kg À1. Following administration of moxidectin, plasma and milk concentrations of moxidectin increased to reach maximal concentrations (C max) of 5.46 AE 3.50 and 23.76 AE 16.63 ng ml À1 at T max of 1.20 AE 0.33 and 1.87 AE 0.77 days in plasma and milk, respectively. The mean residence time (MRT) were similar for plasma and milk (5.27 AE 0.45 and 5.87 AE 0.80 days, respectively). The AUC value was 5-fold higher in milk (109.68 AE 65.01 ng day ml À1) than in plasma (23.66 AE 12.26 ng day ml À1). The ratio of AUC milk/plasma for moxidectin was 5.04 AE 2.13. The moxidectin systemic availability (expressed as plasma AUC values) obtained in buffaloes was in the same range than those reported in cattle. The faster absorption and elimination processes of moxidectin were probably due to a lower storage in fat associated with the fact that animals were in lactation. Nevertheless, due to its high excretion in milk and its high detected maximum concentration in milk which is equivalent or higher to the Maximal Residue Level value (MRL) (40 ng ml À1), its use should be prohibited in lactating buffaloes. Concerning eprinomectin, the C max were of 2.74 AE 0.89 and 3.40 AE 1.68 ng ml À1 at T max of 1.44 AE 0.20 and 1.33 AE 0.0.41 days in plasma and milk, respectively. The MRT and the AUC were similar for plasma (3.17 AE 0.41 days and 11.43 AE 4.01 ng day ml À1) and milk (2.70 AE 0.44 days and 8.49 AE 3.33 ng day ml À1). The ratio of AUC milk/plasma for eprinomectin was 0.76 AE 0.16. The AUC value is 20 times lower than that reported in dairy cattle. The very low extent of mammary excretion and the milk levels reported lower than the MRL (20 ng ml À1) supports the permitted use of eprinomectin in lactating water buffaloes.
The expression of cytochrome P4501Al and IA2 was investigated in rabbit hepatocytes maintained in... more The expression of cytochrome P4501Al and IA2 was investigated in rabbit hepatocytes maintained in primary cultures for 96 hr in the absence or presence of 100 phi of the benzimidazole anthelmintics oxfendazole or fenbendazole. Total cytochrome P-450, ethoxyresorufin 0-deethylase and acetanilide hydroxylase activities were significantly increased in cell cultures receiving benzimidazoles. These increases were more marked after exposure of cultured hepatocytes to oxfendazole (OFZ) than to fenbendazole (FBZ). Western and Northern blot analysis of microsomes and RNA prepared from these cultures revealed increased levels of both protein and specific mRNA for P45OIAl. The inhibition of these inductions in the presence of actinomycin D suggests a transcriptional way of activation of this gene. l%e ability of OFZ to bind to the Ah receptor has been examined. Data obtained from competition experiments with dioxin demonstrated that OFZ and other compounds in the benzimidazole series are not ligand of the Ah receptor. From saturation experiments and Scatchard plot analysis, rabbit hepatocyte Ah receptor (& = 10.6 nM) seems to belong, as does the human Ah receptor, to a low-affinity category. Different induction rates obtained with several henzimidazole drugs suggest that the sulfur atom within the molecule is critical for CYP IA 1 induction. The widely used benzimidazole anthelmintics OFZ and FBZ may exert an inducing effect through an original pathway that does not require a specific binding step to the Ah receptor.
Eprinomectin is only available as a topically applied anthelmintic for dairy cattle. To determine... more Eprinomectin is only available as a topically applied anthelmintic for dairy cattle. To determine whether eprinomectin can be administered in the goat as an injectable formulation, it was subcutaneously delivered to six goats and measured in the plasma at different times after administration. The area under the concentration-time curve (AUC) reported after subcutaneous administration of 0.2 mg kg-1 eprinomectin (68.5±23.2 ng day-1 ml-1) was similar to the AUC previously reported for goats after a pour-on administration of 0.5 mg kg-1 eprinomectin. Thus, our results clearly show that subcutaneous administration is 2.5 times more effective than pour-on administration, in terms of amount of drug present in the organism. This work should encourage the development of a subcutaneous formulation of eprinomectin and should contribute to defining optimal therapeutic conditions for goat anthelmintic treatment.
The plasma levels and milk excretion of eprinomectin were determined in goats following topical a... more The plasma levels and milk excretion of eprinomectin were determined in goats following topical application at doses of 0.5 mg kg)1 and 1.0 mg kg)1. The area under the concentration±time curve (AUC) was 2 times lower for 0.5 mg kg)1 (8.24 3.50 ng day)1 ml)1) than for 1.0 mg kg)1 (15.68 8.84 ng day)1 ml)1), suggesting that the pharmacokinetics of eprinomectin in goats is dose independent. The bioavailability of eprinomectin in lactating compared with non-lactating goats is low. This is probably due to the physiological status of dairy animals, which present a marked decrease in body fat. Comparison of the eprinomectin concentrations in the milk and plasma demonstrated a parallel disposition of the drug with a milk-to-plasma ratio of 0.10±0.25. The amount of drug recovered in the milk was 0.3±0.5% of the total administered dose. In all cases, the maximum level of residue in milk remained below the maximum acceptable level of 30 ng ml)1 permitted in lactating cattle.
Most pharmacokinetic studies on anthelmintic drugs have been performed on non-parasitized animals... more Most pharmacokinetic studies on anthelmintic drugs have been performed on non-parasitized animals. However, it seems likely that the parasite burden could influence the deposition of such drugs. The pharmacokinetics of moxidectin administered orally and by subcutaneous injection was compared in lambs exposed to nematode infection and in parasite naive lambs. Plasma samples were analyzed for moxidectin over 40 days post-treatment. The main pharmacokinetic parameters calculated demonstrated a significant change in drug deposition in infected lambs when compared to controls. The area under the plasma concentration-time curve was decreased 54% and 46% by infection in the subcutaneous and oral groups, respectively. There was also a major decrease in the mean residence time in parasitized lambs. In parallel, the clearance of the drug was increased by infection. Thus, parasite infection dramatically influences the disposition of moxidectin in lambs. These results may contribute to determining a therapeutic strategy adapted to heavily infested animals.
The effect of verapamil, a multidrug-resistance (Mdr)-reversing agent on the absorption of a pour... more The effect of verapamil, a multidrug-resistance (Mdr)-reversing agent on the absorption of a pour-on formulation of ivermectin was evaluated in rats. Absorption of ivermectin was effectively enhanced (40%) by the presence of verapamil, suggesting that absorption of ivermectin involves Mdr-P-glycoprotein and that verapamil should act as a competitive inhibitor for the transport and extrusion of ivermectin by P-glycoprotein. This hypothesis is consistent with other studies describing verapamil as a blocking agent of P-glycoprotein involved in the efflux of ivermectin in a resistant strain of Haemonchus contortus.
Veterinary Research Communications - VET RES COMMUN, 2001
Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. No data w... more Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. No data were available on its metabolism in wild species or in monogastrics. The in vitro metabolism of 14C-moxidectin was studied using hepatic microsomes from several different species: cow (Bos taurus), sheep (Ovis ovis), goat (Capra hircus), deer (Cervus dama), rat (Rattus norvegicus), pig (Sus scrofa and rabbit (Oryctolagus cuniculus). After separation and quantification by HPLC, the extent of metabolism of 14C-moxidectin was greatest with microsomes from sheep (32.7%) as compared to those from cows (20.6%), deer (15.4%), goats (12.7%), rabbits (7.0%) or rats (3.0%). The least metabolism occurred with microsomes from pigs, with 0.8% of total detected metabolites. A C29 monohydroxymethyl metabolite was detected in the greatest amounts, providing 0.4% out of the total detected radioactivity in pigs and 19.3% in sheep. In addition, the importance of P450 3A in the metabolism of 14C-moxidectin w...
SUMMARYP-glycoprotein (P-gp) homologues, belonging to the ATP Binding Cassette (ABC) transporter ... more SUMMARYP-glycoprotein (P-gp) homologues, belonging to the ATP Binding Cassette (ABC) transporter family, are thought to play an important role in the resistance of gastro-intestinal nematode parasites against macrocyclic lactones. The aim of this study was to investigate the influence of various P-gp interfering compounds on the efficacy of ivermectin (IVM) in sensitive and resistant nematode isolates. The feeding of IVM resistant and sensitiveTeladorsagia circumcinctaandHaemonchus contortusfirst-stage larvae (L1) was assessed using a range of IVM concentrations (0·08–40 nm) with or without P-gp inhibitors: valspodar, verapamil, quercetin, ketoconazole and pluronic P85. The P-gp inhibitors were selected on the basis of their ability to interfere with P-gp transport activity in an epithelial cell line over-expressing murine P-gp. In the presence of P-gp interfering agents, thein vitrosusceptibility to IVM of both sensitive and resistant isolates ofT. circumcinctaandH. contortuswas in...
Journal of Veterinary Pharmacology and Therapeutics, 2006
The interaction of moxidectin (a macrocyclic lactone, ML) with P-glycoprotein (P-gp), multidrug r... more The interaction of moxidectin (a macrocyclic lactone, ML) with P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs) and breast cancer resistance protein (BCRP) was studied in primary cultures of rat hepatocytes by measuring the intracellular accumulation of [ 14 C]-moxidectin over 72 h in the presence of specific inhibitors: for P-gp, verapamil (10 lM); for MRPs, MK571 (100 lM), indomethacin (10 lM) and probenecid (3.8 mM); and for BCRP, fumitremorgin C (5 lM). The P-gp and MRP inhibitors increased significantly (P < 0.01) by 48.7%, 49.8%, 49.9% and 57.2% the area under the timeintracellular concentration curve (AUC) of moxidectin in rat hepatocytes, while the BCRP inhibitor, fumitremorgin C, had no effect on the AUC compared with the control. In addition, the mRNAs of all the drug transporters studied were detected in rat hepatocytes from 0 to 72 h. Using this cellular model it has been shown that MRP inhibitors increase moxidectin intracellular concentrations to a similar extent as the P-gp inhibitor. The identification of all the transporters that interact with MLs remains a challenge, which currently concerns several important therapeutic fields.
Journal of Veterinary Pharmacology and Therapeutics, 2001
Moxidectin (MOX) is an antiparasitic drug widely used in cattle, sheep and companion animals. As ... more Moxidectin (MOX) is an antiparasitic drug widely used in cattle, sheep and companion animals. As a result of the implication of cytochrome P450 3 A in the metabolism of MOX and the role of competitor substrates of P-glycoprotein (Pgp) in modi®cation of the bioavailability of endectocides, we studied the in¯uence of verapamil (a multidrug-resistance reversing agent) on the metabolism of 14 C moxidectin in cultured rat hepatocytes over 72 h. The metabolism of MOX remained low: 10.79 1.99% of the total 14 C moxidectin for the main detected metabolite in verapamil-treated cells and 7.17 0.74% for the control cells after 24 h. The main detected metabolite in rat hepatocytes was the same as that detected in rat hepatic microsomes (the C 29 monohydroxymethyl metabolite). Verapamil increased the quantity of MOX in the cells after 24, 48 and 72 h. Examination of the Area Under the concentration time Curve (AUC) of the main detected metabolite revealed a signi®cant increase in the exposure of cells to MOX after verapamil treatment throughout the experiment. It is hypothesized that verapamil interfered with MOX as a substrate for Pgp during the initial incubation period. After this initial interaction, verapamil metabolites were able to interfere with Pgp. This experiment demonstrated the implication of Pgp in the transport of MOX and allowed prediction of the drug±drug interactions which might modify the bioavailability of endectocides.
Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to th... more Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to the involvement of P-glycoprotein (P-gp) and cytochrome P450 3A in the metabolism of moxidectin, we studied the influence of various P-gp interfering agents (ivermectin, quercetin and ketoconazole) on the metabolism of 14C moxidectin in cultured rat hepatocytes over 72 h. This in vitro study allowed selection of compounds which are able to increase the moxidectin bioavailability in lambs. From this, the modulation of moxidectin pharmacokinetics in plasma of lambs was studied after co-administration of 0.2 mg kg(-1) moxidectin (subcutaneously (SC)) and 0.2 mg kg(-1) ivermectin (SC), or 10 mg kg(-1) quercetin (SC), or 10 mg kg(-1) ketoconazole (orally). Ivermectin and quercetin increased significantly the quantity of 14C moxidectin in the rat hepatocytes. Ketoconazole co-administration led to a higher concentration of moxidectin in the rat hepatocytes. In vivo, only quercetin was able to modify the pharmacokinetics of moxidectin in plasma of lambs by increasing significantly the area under the plasma concentration-time curve. This study allowed the use of a natural agent, quercetin, to improve the bioavailability of moxidectin.
Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to th... more Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to the involvement of P-glycoprotein (P-gp) and cytochrome P450 3A in the metabolism of moxidectin, we studied the influence of various P-gp interfering agents (ivermectin, quercetin and ketoconazole) on the metabolism of 14C moxidectin in cultured rat hepatocytes over 72 h. This in vitro study allowed selection of compounds which are able to increase the moxidectin bioavailability in lambs. From this, the modulation of moxidectin pharmacokinetics in plasma of lambs was studied after co-administration of 0.2 mg kg(-1) moxidectin (subcutaneously (SC)) and 0.2 mg kg(-1) ivermectin (SC), or 10 mg kg(-1) quercetin (SC), or 10 mg kg(-1) ketoconazole (orally). Ivermectin and quercetin increased significantly the quantity of 14C moxidectin in the rat hepatocytes. Ketoconazole co-administration led to a higher concentration of moxidectin in the rat hepatocytes. In vivo, only quercetin was able to modify the pharmacokinetics of moxidectin in plasma of lambs by increasing significantly the area under the plasma concentration-time curve. This study allowed the use of a natural agent, quercetin, to improve the bioavailability of moxidectin.
The parasiticide ivermectin and the antifungal drug ketoconazole are drugs that interact with P-g... more The parasiticide ivermectin and the antifungal drug ketoconazole are drugs that interact with P-glycoprotein. We have tested the ability of ketoconazole at a clinical dose to modify the pharmacokinetics of ivermectin in sheep. Lacaune lambs were administered with a single oral dose of ivermectin alone at 0.2 mg/kg (n = 5) or in combination with a daily oral dose of ketoconazole (10 mg/kg) given for 3 days before and 2 days after the ivermectin (n = 5). The plasma kinetics of ivermectin and its metabolite were followed over 15 days by HPLC analysis. Co-administration of ketoconazole induced higher plasma concentrations of ivermectin, leading to a substantial increase in the overall exposure of the animals to the drug. Ketoconazole did not reduce the production of the main ivermectin metabolite but it may rather act by inhibiting P-glycoprotein, and thus increasing the absorption of ivermectin. The use of a P-gp reversing agent such as ketoconazole could be useful tool to optimize antiparasitic therapy in the face of the worldwide development of anthelmintic resistance.
The cytochrome P450 (P450) superfamily represents a group of relevant enzymes in the field of dru... more The cytochrome P450 (P450) superfamily represents a group of relevant enzymes in the field of drug metabolism and several exogenous or constitutional factors contribute to regulate its expression. Cattle represent an important source of animal-derived food-products and studies concerning the P450 expression are needed for the extrapolation of pharmacotoxicological data from one species to another and for the evaluation of the consumer's risk associated with the consumption of harmful residues found in foodstuffs. In the present study, possible breed-, genderand species-differences in P4503A (the P450 subfamily more expressed in the human liver) expression were studied in vitro in Piedmontese (PDM) and Limousin (LIM) meat cattle breeds of both sexes and in domestic Ruminants (cattle, sheep and goats). Cytochrome P450 and P4503A contents as well as CYP3A-dependent drug metabolising enzymes (DME) were measured in liver microsomes. Significant lower levels of P450 (P < 0.001) and P4503A (P < 0.05) contents were observed in PDM vs. LIM of both sexes; the P4503A-dependent DME activities were significantly (P values ranging from 0.05 up to 0.001) higher in PDM cattle, particularly in males. A gendereffect in DME activities was noticed (P < 0.05) only in PDM male cattle. With regards to the species, the expression of both P4503A apoprotein and some of the related DME activities were more pronounced in sheep (P < 0.01 vs. cattle) and in goats (P < 0.05 vs. sheep; P < 0.01 vs. cattle) than in cattle. The significant differences in P4503A expression observed in LIM and PDM cattle are consistent with previously published data on strain-and breed-differences pointed out in rats and men. As far as a possible sex-effect is concerned, no clear-cut evidence is likely to be drawn. Finally, P4503A expression was more relevant in small ruminants. ruminants / liver drug metabolism / CYP3A / gender / breed
Some pharmacokinetic parameters of selamectin were determined in male (n = 5) and female (n = 5) ... more Some pharmacokinetic parameters of selamectin were determined in male (n = 5) and female (n = 5) Beagle dogs following a topical application at a dose rate of 6 mg/kg. The plasma concentration versus time data for the drug were analysed using a one-compartment model. The maximum plasma concentrations of 12.72+5.13 ng/ml for males and 22.65+11.95 ng/ml for females occurred around 5 days after administration. The area under the concentration^time curve (AUC) was 192.08+63.85 ng.day/ml for males and 370.97+146.87 ng.day/ml for females. The mean residence time was the same in males and females (12.55 days). This study reveals a sex-in£uence on the disposition of selamectin in the plasma of dogs, which implies that further information will be needed for correlation with e¤cacy studies in dogs.
The plasma kinetics disposition of moxidectin following a subcutaneous administration with a long... more The plasma kinetics disposition of moxidectin following a subcutaneous administration with a long-acting formulation (Cydectin 1 10%, Fort Dodge Animal Health, France) at the recommended dose of 1 mg kg À1 body weight was evaluated in Charolais cattle breed (five females weighing 425-450 kg) for 120 days. Furthermore, its concentration was measured in hair for the same period. After plasma extraction and derivatization, samples were analysed by HPLC with fluorescence detection. Moxidectin was first detected at 1 h after treatment for plasma (2.00 AE 1.52 ng ml À1) and at 2 days for hair (446.44 AE 193.26 ng g À1). The peak plasma concentration (C max) was 55.71 AE 15.59 ng ml À1 and 444.44 AE 190.45 ng g À1 for plasma and hair, respectively. The mean calculated time of peak occurrence (T max) was 3.40 AE 3.36 and 2 days for plasma and hair, respectively. The mean residence time (MRT) was 28.93 AE 2.87 and 13.32 AE 2.48 days for plasma and hair cattle. The area under concentration-time curve (AUC) was 1278.95 AE 228.92 ng day ml À1 and 2663.82 AE 1096.62 ng day g À1 for plasma and hair, respectively. At the last sampling time (120 days), the concentration was 1.91 AE 0.26 ng ml À1 and 0.69 AE 0.52 ng g À1 for plasma and hair, respectively. The bioavailability of this long-acting formulation of moxidectin is similar to that registered after subcutaneous administration of moxidectin in cattle at 0.2 mg kg À1 body weight. For the first time the moxidectin pharmacokinetics parameters in hair after a subcutaneous administration was described. The moxidectin profile concentrations in hair reflected that registered in plasma. The previous studies of efficacy have to be correlated to the extended period of absorption and distribution by the LA formulation due to the fivefold higher dose rate in comparison with the 1% injectable formulation (0.2 mg kg À1 body weight).
The pharmacokinetics and mammary excretion of moxidectin and eprinomectin were determined in wate... more The pharmacokinetics and mammary excretion of moxidectin and eprinomectin were determined in water buffaloes (Bubalus bubalis) following topical administration of 0.5 mg kg À1. Following administration of moxidectin, plasma and milk concentrations of moxidectin increased to reach maximal concentrations (C max) of 5.46 AE 3.50 and 23.76 AE 16.63 ng ml À1 at T max of 1.20 AE 0.33 and 1.87 AE 0.77 days in plasma and milk, respectively. The mean residence time (MRT) were similar for plasma and milk (5.27 AE 0.45 and 5.87 AE 0.80 days, respectively). The AUC value was 5-fold higher in milk (109.68 AE 65.01 ng day ml À1) than in plasma (23.66 AE 12.26 ng day ml À1). The ratio of AUC milk/plasma for moxidectin was 5.04 AE 2.13. The moxidectin systemic availability (expressed as plasma AUC values) obtained in buffaloes was in the same range than those reported in cattle. The faster absorption and elimination processes of moxidectin were probably due to a lower storage in fat associated with the fact that animals were in lactation. Nevertheless, due to its high excretion in milk and its high detected maximum concentration in milk which is equivalent or higher to the Maximal Residue Level value (MRL) (40 ng ml À1), its use should be prohibited in lactating buffaloes. Concerning eprinomectin, the C max were of 2.74 AE 0.89 and 3.40 AE 1.68 ng ml À1 at T max of 1.44 AE 0.20 and 1.33 AE 0.0.41 days in plasma and milk, respectively. The MRT and the AUC were similar for plasma (3.17 AE 0.41 days and 11.43 AE 4.01 ng day ml À1) and milk (2.70 AE 0.44 days and 8.49 AE 3.33 ng day ml À1). The ratio of AUC milk/plasma for eprinomectin was 0.76 AE 0.16. The AUC value is 20 times lower than that reported in dairy cattle. The very low extent of mammary excretion and the milk levels reported lower than the MRL (20 ng ml À1) supports the permitted use of eprinomectin in lactating water buffaloes.
The expression of cytochrome P4501Al and IA2 was investigated in rabbit hepatocytes maintained in... more The expression of cytochrome P4501Al and IA2 was investigated in rabbit hepatocytes maintained in primary cultures for 96 hr in the absence or presence of 100 phi of the benzimidazole anthelmintics oxfendazole or fenbendazole. Total cytochrome P-450, ethoxyresorufin 0-deethylase and acetanilide hydroxylase activities were significantly increased in cell cultures receiving benzimidazoles. These increases were more marked after exposure of cultured hepatocytes to oxfendazole (OFZ) than to fenbendazole (FBZ). Western and Northern blot analysis of microsomes and RNA prepared from these cultures revealed increased levels of both protein and specific mRNA for P45OIAl. The inhibition of these inductions in the presence of actinomycin D suggests a transcriptional way of activation of this gene. l%e ability of OFZ to bind to the Ah receptor has been examined. Data obtained from competition experiments with dioxin demonstrated that OFZ and other compounds in the benzimidazole series are not ligand of the Ah receptor. From saturation experiments and Scatchard plot analysis, rabbit hepatocyte Ah receptor (& = 10.6 nM) seems to belong, as does the human Ah receptor, to a low-affinity category. Different induction rates obtained with several henzimidazole drugs suggest that the sulfur atom within the molecule is critical for CYP IA 1 induction. The widely used benzimidazole anthelmintics OFZ and FBZ may exert an inducing effect through an original pathway that does not require a specific binding step to the Ah receptor.
Eprinomectin is only available as a topically applied anthelmintic for dairy cattle. To determine... more Eprinomectin is only available as a topically applied anthelmintic for dairy cattle. To determine whether eprinomectin can be administered in the goat as an injectable formulation, it was subcutaneously delivered to six goats and measured in the plasma at different times after administration. The area under the concentration-time curve (AUC) reported after subcutaneous administration of 0.2 mg kg-1 eprinomectin (68.5±23.2 ng day-1 ml-1) was similar to the AUC previously reported for goats after a pour-on administration of 0.5 mg kg-1 eprinomectin. Thus, our results clearly show that subcutaneous administration is 2.5 times more effective than pour-on administration, in terms of amount of drug present in the organism. This work should encourage the development of a subcutaneous formulation of eprinomectin and should contribute to defining optimal therapeutic conditions for goat anthelmintic treatment.
The plasma levels and milk excretion of eprinomectin were determined in goats following topical a... more The plasma levels and milk excretion of eprinomectin were determined in goats following topical application at doses of 0.5 mg kg)1 and 1.0 mg kg)1. The area under the concentration±time curve (AUC) was 2 times lower for 0.5 mg kg)1 (8.24 3.50 ng day)1 ml)1) than for 1.0 mg kg)1 (15.68 8.84 ng day)1 ml)1), suggesting that the pharmacokinetics of eprinomectin in goats is dose independent. The bioavailability of eprinomectin in lactating compared with non-lactating goats is low. This is probably due to the physiological status of dairy animals, which present a marked decrease in body fat. Comparison of the eprinomectin concentrations in the milk and plasma demonstrated a parallel disposition of the drug with a milk-to-plasma ratio of 0.10±0.25. The amount of drug recovered in the milk was 0.3±0.5% of the total administered dose. In all cases, the maximum level of residue in milk remained below the maximum acceptable level of 30 ng ml)1 permitted in lactating cattle.
Most pharmacokinetic studies on anthelmintic drugs have been performed on non-parasitized animals... more Most pharmacokinetic studies on anthelmintic drugs have been performed on non-parasitized animals. However, it seems likely that the parasite burden could influence the deposition of such drugs. The pharmacokinetics of moxidectin administered orally and by subcutaneous injection was compared in lambs exposed to nematode infection and in parasite naive lambs. Plasma samples were analyzed for moxidectin over 40 days post-treatment. The main pharmacokinetic parameters calculated demonstrated a significant change in drug deposition in infected lambs when compared to controls. The area under the plasma concentration-time curve was decreased 54% and 46% by infection in the subcutaneous and oral groups, respectively. There was also a major decrease in the mean residence time in parasitized lambs. In parallel, the clearance of the drug was increased by infection. Thus, parasite infection dramatically influences the disposition of moxidectin in lambs. These results may contribute to determining a therapeutic strategy adapted to heavily infested animals.
The effect of verapamil, a multidrug-resistance (Mdr)-reversing agent on the absorption of a pour... more The effect of verapamil, a multidrug-resistance (Mdr)-reversing agent on the absorption of a pour-on formulation of ivermectin was evaluated in rats. Absorption of ivermectin was effectively enhanced (40%) by the presence of verapamil, suggesting that absorption of ivermectin involves Mdr-P-glycoprotein and that verapamil should act as a competitive inhibitor for the transport and extrusion of ivermectin by P-glycoprotein. This hypothesis is consistent with other studies describing verapamil as a blocking agent of P-glycoprotein involved in the efflux of ivermectin in a resistant strain of Haemonchus contortus.
Veterinary Research Communications - VET RES COMMUN, 2001
Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. No data w... more Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. No data were available on its metabolism in wild species or in monogastrics. The in vitro metabolism of 14C-moxidectin was studied using hepatic microsomes from several different species: cow (Bos taurus), sheep (Ovis ovis), goat (Capra hircus), deer (Cervus dama), rat (Rattus norvegicus), pig (Sus scrofa and rabbit (Oryctolagus cuniculus). After separation and quantification by HPLC, the extent of metabolism of 14C-moxidectin was greatest with microsomes from sheep (32.7%) as compared to those from cows (20.6%), deer (15.4%), goats (12.7%), rabbits (7.0%) or rats (3.0%). The least metabolism occurred with microsomes from pigs, with 0.8% of total detected metabolites. A C29 monohydroxymethyl metabolite was detected in the greatest amounts, providing 0.4% out of the total detected radioactivity in pigs and 19.3% in sheep. In addition, the importance of P450 3A in the metabolism of 14C-moxidectin w...
SUMMARYP-glycoprotein (P-gp) homologues, belonging to the ATP Binding Cassette (ABC) transporter ... more SUMMARYP-glycoprotein (P-gp) homologues, belonging to the ATP Binding Cassette (ABC) transporter family, are thought to play an important role in the resistance of gastro-intestinal nematode parasites against macrocyclic lactones. The aim of this study was to investigate the influence of various P-gp interfering compounds on the efficacy of ivermectin (IVM) in sensitive and resistant nematode isolates. The feeding of IVM resistant and sensitiveTeladorsagia circumcinctaandHaemonchus contortusfirst-stage larvae (L1) was assessed using a range of IVM concentrations (0·08–40 nm) with or without P-gp inhibitors: valspodar, verapamil, quercetin, ketoconazole and pluronic P85. The P-gp inhibitors were selected on the basis of their ability to interfere with P-gp transport activity in an epithelial cell line over-expressing murine P-gp. In the presence of P-gp interfering agents, thein vitrosusceptibility to IVM of both sensitive and resistant isolates ofT. circumcinctaandH. contortuswas in...
Journal of Veterinary Pharmacology and Therapeutics, 2006
The interaction of moxidectin (a macrocyclic lactone, ML) with P-glycoprotein (P-gp), multidrug r... more The interaction of moxidectin (a macrocyclic lactone, ML) with P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs) and breast cancer resistance protein (BCRP) was studied in primary cultures of rat hepatocytes by measuring the intracellular accumulation of [ 14 C]-moxidectin over 72 h in the presence of specific inhibitors: for P-gp, verapamil (10 lM); for MRPs, MK571 (100 lM), indomethacin (10 lM) and probenecid (3.8 mM); and for BCRP, fumitremorgin C (5 lM). The P-gp and MRP inhibitors increased significantly (P < 0.01) by 48.7%, 49.8%, 49.9% and 57.2% the area under the timeintracellular concentration curve (AUC) of moxidectin in rat hepatocytes, while the BCRP inhibitor, fumitremorgin C, had no effect on the AUC compared with the control. In addition, the mRNAs of all the drug transporters studied were detected in rat hepatocytes from 0 to 72 h. Using this cellular model it has been shown that MRP inhibitors increase moxidectin intracellular concentrations to a similar extent as the P-gp inhibitor. The identification of all the transporters that interact with MLs remains a challenge, which currently concerns several important therapeutic fields.
Journal of Veterinary Pharmacology and Therapeutics, 2001
Moxidectin (MOX) is an antiparasitic drug widely used in cattle, sheep and companion animals. As ... more Moxidectin (MOX) is an antiparasitic drug widely used in cattle, sheep and companion animals. As a result of the implication of cytochrome P450 3 A in the metabolism of MOX and the role of competitor substrates of P-glycoprotein (Pgp) in modi®cation of the bioavailability of endectocides, we studied the in¯uence of verapamil (a multidrug-resistance reversing agent) on the metabolism of 14 C moxidectin in cultured rat hepatocytes over 72 h. The metabolism of MOX remained low: 10.79 1.99% of the total 14 C moxidectin for the main detected metabolite in verapamil-treated cells and 7.17 0.74% for the control cells after 24 h. The main detected metabolite in rat hepatocytes was the same as that detected in rat hepatic microsomes (the C 29 monohydroxymethyl metabolite). Verapamil increased the quantity of MOX in the cells after 24, 48 and 72 h. Examination of the Area Under the concentration time Curve (AUC) of the main detected metabolite revealed a signi®cant increase in the exposure of cells to MOX after verapamil treatment throughout the experiment. It is hypothesized that verapamil interfered with MOX as a substrate for Pgp during the initial incubation period. After this initial interaction, verapamil metabolites were able to interfere with Pgp. This experiment demonstrated the implication of Pgp in the transport of MOX and allowed prediction of the drug±drug interactions which might modify the bioavailability of endectocides.
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