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Bioavailability of albendazole sulphoxide after netobimin administration in sheep: effects of fenbendazole coadministration.
Research in Veterinary Science 1999, 66, 281–283 Article No. rvsc.1998.0276, available online at http://idealibrary.com on
SHORT COMMUNICATION
Bioavailability of albendazole sulphoxide after netobimin administration in sheep: effects of fenbendazole coadministration. G. MERINO, A.I. ALVAREZ, P.A. REDONDO, J.L. GARCIA, O.M. LARRODÉ, J.G. PRIETO. Laboratory of Animal Physiology. Faculty of Veterinary. University of León. E24071, León, Spain.
SUMMARY After oral co-administration of two dosages of netobimin (7·5 and 20 mg kg–1 with fenbendazole (1·1 mg kg–1) to Merino sheep, the AUC0-∞ of albendazole sulphoxide at the lower dosage of netobimin, was significantly increased (75·5 per cent) from control value (34·43 ± 7·91 versus 60·33 ± 11·93 µg h ml–1). The pharmacokinetic parameters MRT and T1/2 were also increased: 18·96 ± 2·54 vs 26·44 ± 4·69 h and 10·31 ± 1·72 vs 22·28 ± 6·75 h respectively. No data corresponding to the higher dosage of netobimin (20 mg kg–1) were statistically different from control values. It is concluded that fenbendazole increases the bioavailability of albendazole sulphoxide in sheep at the 7·5 mg kg–1 dosage, and this may produce a potentiated anthelmintic action.
NETOBIMIN (NTB) is an anthelmintic prodrug which is converted into albendazole by the gastrointestinal microflora after oral administration to sheep (Delatour et al 1986). Albendazole (ABZ) is oxidised, by liver microsomal systems, into its pharmacologically active metabolite, albendazole sulphoxide (ABZSO), and in a second step to albendazole sulphone (ABZSO2), an inactive metabolite. The pharmacokinetic behaviour of netobimin and albendazole is well documented in sheep (Lanusse and Prichard 1990). The low solubility of benzimidazole drugs and their limited absorption from the gut, result in low bioavailability. Netobimin is an interesting prodrug since it can be prepared as an ionic salt with good water solubility. Fenbendazole (FBZ), another widely used benzimidazole in veterinary medicine, acts as competitive inhibitor of albendazole sulphoxidase activity when it is incubated in vitro using liver microsomal preparations with albendazole as substrate (FBZ inhibitory constant = 243 µM) (Galtier et al 1986). The present in vivo study was designed to describe the pharmacokinetic parameters of albendazole metabolites in sheep, when different netobimin oral doses were co-administered with fenbendazole (1·1 mg kg–1 equivalent to 375 µM). The aim of this work is to determine whether fenbendazole could be used to improve the pharmacokinetic profile of netobimin. Female Merino sheep weighing 48·5 ± 6·5 kg were used in this trial. Animals were parasite-free and fed with hay and water ad libitum. Sheep were allocated into two groups. The study was conducted in two phases: Phase I: animals were treated with netobimin (Hapasil®, Schering Plough S.A., Madrid, Spain) by oral administration of 7·5 mg (six animals) and 20 mg kg–1 body weight (four animals). Phase II: After a wash-out period of one month, the same animals were treated with the same formulations and dosages of netobimin plus 1·1 mg kg–1 of fenbendazole (Panacur®, Hoechst lbérica S.A., Madrid, Spain). Fenbendazole was given in a suspension with netobimin. All treatments were administered as a single dose orally. Blood samples were collected from the jugular vein into heparinized vacutainers during 120 hours after treatment. Blood was centrifuged inmediately and plasma collected and frozen at –20°C until the time of drug analysis. Analysis of plasma for albendazole, albendazole sulphoxide and albendazole sulphone was carried out by high performance liquid chromatography (Redondo et al 1998). Parent netobimin was not detectable in the plasma samples (< 0·4 µg ml–1). These results are 0034-5288/99/030281 + 03 $18.00/0
in accordance with data of Delatour et al 1986 following oral administration in sheep. Pharmacokinetic analysis for albendazole sulphoxide and albendazole sulphone were carried out by using PKCALC software with a non-compartmental model (Shumaker 1986). The pharmacokinetic parameters are presented as mean ± S.D. Mean pharmacokinetic parameters for each formulation were compared by analysis of variance (ANOVA). Whenever a significant F-value was obtained, a Newman-Keuls multiple range test was performed to indicate the order of significance. Values of P ≤ 0·05 were considered statistically significant. The plasma concentration versus time profile of the major metabolite, albendazole sulphoxide, obtained by the administration of each formulation is shown in Fig 1. There was a clear difference in the curve profile after administration of netobimin at 7·5 mg kg–1 alone and the curve after coadministration with fenbendazole. However, in the case of the netobimin 20 mg kg–1 and netobimin plus fenbendazole, this difference was not observed and the plasma curve is similar to the control. The pharmacokinetic parameters of albendazole sulphoxide obtained with the different netobimin treatments are displayed in Table 1. Statistical comparison was carried out between each treatment of netobimin alone and with fenbendazole. Netobimin and albendazole were efficiently converted by the ruminal flora and the hepatic metabolic system of the sheep, these prevented the detection of these two compounds in the plasma in all formulations and at all sampling times. The alteration of albendazole oxidative metabolism by the coadministration of fenbendazole resulted in significant changes in the pharmacokinetic patterns of albendazole sulphoxide in sheep. When 1·1 mg kg–1 of fenbendazole was used with a dosage of 7·5 mg kg–1 of netobimin, the area under the concentration–time curve (AUC0-∞) of albendazole sulphoxide showed a 75·5 per cent increase from control value (AUC0-∞ 34·43 ± 7·91 versus 60·33 ± 11·93 µg h ml–1), while there was no difference in the AUC0-∞ ratio albendazole sulphone/albendazole sulphoxide from the control value (Table 1). The increase in the AUC0-∞ of the albendazole sulphoxide could be the result of several mechanisms: firstly, it has been reported that fenbendazole causes inhibition of the albendazole sulphoxidation by liver microsomes in vitro because both drugs are biotransformed by the same enzyme system (Galtier et al 1986, Benchaoui and McKellar 1996). Albendazole is converted into albendazole © 1999 W. B. Saunders Company Ltd
G. Merino, A.I. Alvarez, P.A. Redondo, J.L. Garcia, O.M. Larrodé, J.G. Prieto
282
7·5 mg kg–1 7·5 mg kg–1 +FBZ
1·0
0·1
20 mg kg–1
10·0 Plasmatic concentration (µg ml–1)
Plasmatic concentration (µg ml–1)
10·0
20 mg kg–1 +FBZ
1·0
0·1 0
20
40 Time (h)
60
0
80
20
40
60
80
Time (h)
FIG 1: Plasma concentrations of albendazole sulphoxide (ABZSO) following administration of netobimin alone (n=6) or with fenbendazole (FBZ) (n=4) in sheep.
Table 1:
Pharmacokinetic parameters (mean + SD) of albendazole sulphoxide after administration of netobimin with or without fenbendazole.
(0-∞) µg h.ml–1) (h) T 1/2 (h) Tmax (h) Cmax (µg.ml–1) Cmax/AUC (0-∞) AUC(ABZSO2)/AUC(ABZSO)
AUC
MRT
7·5 mg kg–1
7·5 mg kg–1 + FBZ
20 mg kg–1
34·45 (7·91) 18·96 (2·54) 10·31 (1·72) 9·00 (1·67) 1·34 (0·31) 0·055 (0·007) 0·69 (0·04)
60·53 (11·93*) 26·44 (4·69*) 22·28 (6·75*) 9·33 (2·07) 1·52 (0·09) 0·035 (0·013*) 0·75 (0·12)
107·22 (14·79) 20·36 (2·74) 8·95 (3·12) 11·50 (3·00) 3·59 (0·62) 0·031 (0·005) 0·54 (0·09)
20 mg kg–1 + FBZ 116·19 (53·21) 24·22 (4·16) 14·45 (2·00) 15·00 (3·83) 3·31 (1·07) 0·029 (0·004) 0·50 (0·07)
* Significant difference (P ≤ 0·05) between each treatment of netobimin alone and with fenbendazole TABLE 2: Pharmacokinetic parameters (mean ± SD) of albendazole sulphone after administration of netobimin with or without fenbendazole.
(0-∞) (µg h.ml–1) (h) T 1/2 (h) Tmax (h) Cmax (µg.ml–1) AUC
MRT
7·5 mg kg–1
7·5 mg kg–1 + FBZ
23·43 (5·29) 23·31 (2·53) 19·18 (7·17) 20·00 (8·20) 0·53 (0·08)
46·40 (11·82*) 37·26 (7·47*) 53·81 (15·02*) 28·50 (6·86) 0·50 (0·04)
20 mg kg–1 58·16 (16·23) 29·32 (2·17) 14·62 (11·83) 28·00 (3·00) 1·24 (0·18)
20 mg kg–1 + FBZ 55·74 (17·51) 36·58 (9·84) 27·11 (14·72) 20·33 (5·74) 0·88 (0·06*)
* Significant difference (P ≤ 0·05) between each treatment of netobimin alone and with fenbendazole
sulphoxide by two enzyme systems, flavine monooxygenase enzyme system (FMO) and cytochrome P450. Albendazole sulphoxide has two enantiomers (–) and (+), that are produced from the prochiral thioether albendazole and can be separated by HPLC. In sheep, 86 per cent of the plasma AUC is represented by enantiomer albendazole sulphoxide (+), which is generated through the activity of the FMO system (Delatour et al 1991). There is substrate competition between fenbendazole and albendazole for the FMO pathway. Lacey et al (1994) suggested that Cmax/AUC is a better estimation than Cmax as indirect measure of rate of drug absorption in comparative pharmacokinetic studies. So, the decrease of rate of albendazole absorption, that we have obtained, estimated as Cmax/AUC of albendazole sulphoxide, indicates that fenbendazole is delaying the biotransformation rate from albendazole to its metabolite albendazole sulphoxide and as a consequence causing an extended time of albendazole sulphoxide formation. A significant increase of the MRT of sulphoxide was produced. Furthermore, a significantly longer half-life of the terminal exponent (T1/2) was observed when fenbendazole was co-administered
with netobimin and this could influence the increase of AUC0-∞ and MRT. This observation would suggest a saturation of the sulfonation pathway by both anthelmintics because there was no evidence of any change of the albendazole sulphone/albendazole sulphoxide ratio when the AUC0-∞ of albendazole sulphoxide was increased (Table 1). The pharmacokinetic parameters for albendazole sulphone is included in Table 2. Two pharmacokinetic features could help to improve the bioavailability of albendazole sulfoxide. First, albendazole sulphoxide has been shown to be efficiently reduced back to albendazole in the rumen of sheep (Lanusse et al 1992) and fenbendazole is found in the plasma for a longer time after administration than albendazole in sheep (Lanusse et al 1995) which would result in a longer competitive inhibition effect. The lack of effect of FBZ on the higher dose of netobimin could be because the concentration of netobimin is much higher than the one of FBZ and there is no competition at level of sustrate. Similar results have been obtained by Hennessy et al (1985). They observed that the highest increase in the AUC appears when equal dosages of parbendazole and oxfendazole were administered.
Bioavailavility of albendazole sulphoxide in sheep. The efficacy of albendazole and netobimin may be improved by co-administration of metabolic inhibitors which act mainly by increasing the plasma concentration profiles. The methimazole inhibits the FMO system and it has been shown to potentiate netobimin pharmacokinetic profile in sheep (Lanusse and Prichard 1992). Also, the interaction of inhibitors of cytochrome P450 such as cimetidine and piperonyl butoxide has pharmacokinetic implications on relation to albendazole (Wen et al 1994) and fenbendazole (Benchaoui and McKellar 1996). The co-administration of other benzimidazole drugs has shown to potentiate the anthelmintic activity. So, parbendazole increases the disposition of oxfendazole (Hennessy et al 1985, 1992). Fenbendazole coadministered with netobimin also has been used to improve the treatment of secondary hydatid cysts in gerbils (García et al 1997). In conclusion, the co-administration of fenbendazole (1·1 mg kg–1) with netobimin increased the pharmacokinetic disposition of the active metabolite in sheep which may enhance its efficacy against helminthosis.
ACKNOWLEDGEMENTS This work was supported by Junta de Castilla y León (22/12/95).
REFERENCES BENCHAOUI, H.A. & MCKELLAR, Q.A. (1996) Interaction between fenbendazole and piperonyl butoxide: pharmacokinetic and pharmacodynamic implications. Journal of Pharmacy and Pharmacology 48, 753–759. DELATOUR, P., CURE, M.C., BENOIT, E. & GARNIER F. (1986) Netobimin (Totabin-SCH): preliminary investigations on metabolism and pharmacology. Journal of Veterinary Pharmacology and TherapheutiCs 9, 230–234. DELATOUR, P., BENOIT, E., CAUDE, M. & TAMBUTE, A. (1991) Species differences in the generation of the chiral sulfoxide metabolite of albendazole in sheep and rats. Chirality 2, 156–160.
283
GALTIER, P., ALVINERIE, M. & DELATOUR, P. (1986) In vitro sulfoxidation of albendazole by ovine liver microsomes. American Journal of Veterinary Research. 47, 447–450. GARCIA, J.L., ALVAREZ, A.I., REDONDO, P., VOCES, J.A. & PRIETO J.G. (1997) In vivo inhibition of the regenerative capacity of hydatid material after treatment with netobimin. Parasitology Research 83, 105–108. HENNESSY, D.R., LACEY, F., PRICHARD, R.K. & STEEL J.W. (1985) Potentiation of the anthelmintic activity of oxfendazole by parbendazole. J. Vet. Pharmecol. Therap. 8, 270–275. HENNESSY, D.R., STEEL J.W., PRICHARD, R.K. & LACEY, F. (1992) The effect of co-administration of parbendazole on the disposition of oxfendazole. J. Vet. Pharmecol. Therap. 15, 10–18. LACEY, L.F., KEENE, O.N., DUQUESNOY, C. & BYE, A. (1994) Evaluation of different indirect measures of rate of drug absorption in comparative pharmacokinetic studies. Journal of Pharmaceutical Sciences 83, 212–215. LANUSSE, C.E. & PRICHARD, R.K. (1990) Pharmacokinetic behaviour of netobimin and its metabolites in sheep. Journal of Veterinary Pharmacology and Therapheutics 13, 170–178. LANUSSE, C.E. & PRICHARD, R.K. (1992) Methimazole increases the plasma concentrations of albendaZole metabolites of netobimin in sheep. Biopharmaceutics & Drug Disposition 13, 95–103. LANUSSE, C.E., NARE, B., GASCON, L. & PRICHARD, R.K. (1992) Metabolism of albendazole and albendazole sulphoxide by ruminal and intestinal fluids of sheep and cattle. Xenobiotica 22, 419–426. LANUSSE, C.E., GASCON, L.H. & PRICHARD, R.K. (1995) Comparative plasma disposition kinetics of albendazole, fenbendazole, oxfendazole and their metabolites in adult sheep. Journal of Veterinary Pharmacology and Therapeutics 18, 196–203. REDONDO, P.A., ALVAREZ, A.I., GARCIA, J.L., VILLAVERDE, C. & PRIETO, J.G. (1998) Influence of surfactants on oral bioavailability of albendazole based on the formation of the sulphoxide metabolites in rats. Biopharmaceutics and Drug Disposition 19, 65–70. SHUMAKER, R.C. (1986) PKCALC: a BASIC interactive computer program for statistical and pharmacokinetic analysis of data. Drug Metabolism Reviews 17, 331–348. WEN H., ZHANG, H.W., MUHMUT, M., ZOU, P.F., NEW, R.R.C. & CRAIG, P.S. (1994) Initial observation on albendazole in combination with cimetidine for the treatment of human cystic echinococcosis. Annal of Tropical Medicine and Parasitology 88, 49–52.
Accepted February 8, 1999
SHORT COMMUNICATION
Bioavailability of albendazole sulphoxide after netobimin administration in sheep: effects of fenbendazole coadministration. G. MERINO, A.I. ALVAREZ, P.A. REDONDO, J.L. GARCIA, O.M. LARRODÉ, J.G. PRIETO. Laboratory of Animal Physiology. Faculty of Veterinary. University of León. E24071, León, Spain.
SUMMARY After oral co-administration of two dosages of netobimin (7·5 and 20 mg kg–1 with fenbendazole (1·1 mg kg–1) to Merino sheep, the AUC0-∞ of albendazole sulphoxide at the lower dosage of netobimin, was significantly increased (75·5 per cent) from control value (34·43 ± 7·91 versus 60·33 ± 11·93 µg h ml–1). The pharmacokinetic parameters MRT and T1/2 were also increased: 18·96 ± 2·54 vs 26·44 ± 4·69 h and 10·31 ± 1·72 vs 22·28 ± 6·75 h respectively. No data corresponding to the higher dosage of netobimin (20 mg kg–1) were statistically different from control values. It is concluded that fenbendazole increases the bioavailability of albendazole sulphoxide in sheep at the 7·5 mg kg–1 dosage, and this may produce a potentiated anthelmintic action.
NETOBIMIN (NTB) is an anthelmintic prodrug which is converted into albendazole by the gastrointestinal microflora after oral administration to sheep (Delatour et al 1986). Albendazole (ABZ) is oxidised, by liver microsomal systems, into its pharmacologically active metabolite, albendazole sulphoxide (ABZSO), and in a second step to albendazole sulphone (ABZSO2), an inactive metabolite. The pharmacokinetic behaviour of netobimin and albendazole is well documented in sheep (Lanusse and Prichard 1990). The low solubility of benzimidazole drugs and their limited absorption from the gut, result in low bioavailability. Netobimin is an interesting prodrug since it can be prepared as an ionic salt with good water solubility. Fenbendazole (FBZ), another widely used benzimidazole in veterinary medicine, acts as competitive inhibitor of albendazole sulphoxidase activity when it is incubated in vitro using liver microsomal preparations with albendazole as substrate (FBZ inhibitory constant = 243 µM) (Galtier et al 1986). The present in vivo study was designed to describe the pharmacokinetic parameters of albendazole metabolites in sheep, when different netobimin oral doses were co-administered with fenbendazole (1·1 mg kg–1 equivalent to 375 µM). The aim of this work is to determine whether fenbendazole could be used to improve the pharmacokinetic profile of netobimin. Female Merino sheep weighing 48·5 ± 6·5 kg were used in this trial. Animals were parasite-free and fed with hay and water ad libitum. Sheep were allocated into two groups. The study was conducted in two phases: Phase I: animals were treated with netobimin (Hapasil®, Schering Plough S.A., Madrid, Spain) by oral administration of 7·5 mg (six animals) and 20 mg kg–1 body weight (four animals). Phase II: After a wash-out period of one month, the same animals were treated with the same formulations and dosages of netobimin plus 1·1 mg kg–1 of fenbendazole (Panacur®, Hoechst lbérica S.A., Madrid, Spain). Fenbendazole was given in a suspension with netobimin. All treatments were administered as a single dose orally. Blood samples were collected from the jugular vein into heparinized vacutainers during 120 hours after treatment. Blood was centrifuged inmediately and plasma collected and frozen at –20°C until the time of drug analysis. Analysis of plasma for albendazole, albendazole sulphoxide and albendazole sulphone was carried out by high performance liquid chromatography (Redondo et al 1998). Parent netobimin was not detectable in the plasma samples (< 0·4 µg ml–1). These results are 0034-5288/99/030281 + 03 $18.00/0
in accordance with data of Delatour et al 1986 following oral administration in sheep. Pharmacokinetic analysis for albendazole sulphoxide and albendazole sulphone were carried out by using PKCALC software with a non-compartmental model (Shumaker 1986). The pharmacokinetic parameters are presented as mean ± S.D. Mean pharmacokinetic parameters for each formulation were compared by analysis of variance (ANOVA). Whenever a significant F-value was obtained, a Newman-Keuls multiple range test was performed to indicate the order of significance. Values of P ≤ 0·05 were considered statistically significant. The plasma concentration versus time profile of the major metabolite, albendazole sulphoxide, obtained by the administration of each formulation is shown in Fig 1. There was a clear difference in the curve profile after administration of netobimin at 7·5 mg kg–1 alone and the curve after coadministration with fenbendazole. However, in the case of the netobimin 20 mg kg–1 and netobimin plus fenbendazole, this difference was not observed and the plasma curve is similar to the control. The pharmacokinetic parameters of albendazole sulphoxide obtained with the different netobimin treatments are displayed in Table 1. Statistical comparison was carried out between each treatment of netobimin alone and with fenbendazole. Netobimin and albendazole were efficiently converted by the ruminal flora and the hepatic metabolic system of the sheep, these prevented the detection of these two compounds in the plasma in all formulations and at all sampling times. The alteration of albendazole oxidative metabolism by the coadministration of fenbendazole resulted in significant changes in the pharmacokinetic patterns of albendazole sulphoxide in sheep. When 1·1 mg kg–1 of fenbendazole was used with a dosage of 7·5 mg kg–1 of netobimin, the area under the concentration–time curve (AUC0-∞) of albendazole sulphoxide showed a 75·5 per cent increase from control value (AUC0-∞ 34·43 ± 7·91 versus 60·33 ± 11·93 µg h ml–1), while there was no difference in the AUC0-∞ ratio albendazole sulphone/albendazole sulphoxide from the control value (Table 1). The increase in the AUC0-∞ of the albendazole sulphoxide could be the result of several mechanisms: firstly, it has been reported that fenbendazole causes inhibition of the albendazole sulphoxidation by liver microsomes in vitro because both drugs are biotransformed by the same enzyme system (Galtier et al 1986, Benchaoui and McKellar 1996). Albendazole is converted into albendazole © 1999 W. B. Saunders Company Ltd
G. Merino, A.I. Alvarez, P.A. Redondo, J.L. Garcia, O.M. Larrodé, J.G. Prieto
282
7·5 mg kg–1 7·5 mg kg–1 +FBZ
1·0
0·1
20 mg kg–1
10·0 Plasmatic concentration (µg ml–1)
Plasmatic concentration (µg ml–1)
10·0
20 mg kg–1 +FBZ
1·0
0·1 0
20
40 Time (h)
60
0
80
20
40
60
80
Time (h)
FIG 1: Plasma concentrations of albendazole sulphoxide (ABZSO) following administration of netobimin alone (n=6) or with fenbendazole (FBZ) (n=4) in sheep.
Table 1:
Pharmacokinetic parameters (mean + SD) of albendazole sulphoxide after administration of netobimin with or without fenbendazole.
(0-∞) µg h.ml–1) (h) T 1/2 (h) Tmax (h) Cmax (µg.ml–1) Cmax/AUC (0-∞) AUC(ABZSO2)/AUC(ABZSO)
AUC
MRT
7·5 mg kg–1
7·5 mg kg–1 + FBZ
20 mg kg–1
34·45 (7·91) 18·96 (2·54) 10·31 (1·72) 9·00 (1·67) 1·34 (0·31) 0·055 (0·007) 0·69 (0·04)
60·53 (11·93*) 26·44 (4·69*) 22·28 (6·75*) 9·33 (2·07) 1·52 (0·09) 0·035 (0·013*) 0·75 (0·12)
107·22 (14·79) 20·36 (2·74) 8·95 (3·12) 11·50 (3·00) 3·59 (0·62) 0·031 (0·005) 0·54 (0·09)
20 mg kg–1 + FBZ 116·19 (53·21) 24·22 (4·16) 14·45 (2·00) 15·00 (3·83) 3·31 (1·07) 0·029 (0·004) 0·50 (0·07)
* Significant difference (P ≤ 0·05) between each treatment of netobimin alone and with fenbendazole TABLE 2: Pharmacokinetic parameters (mean ± SD) of albendazole sulphone after administration of netobimin with or without fenbendazole.
(0-∞) (µg h.ml–1) (h) T 1/2 (h) Tmax (h) Cmax (µg.ml–1) AUC
MRT
7·5 mg kg–1
7·5 mg kg–1 + FBZ
23·43 (5·29) 23·31 (2·53) 19·18 (7·17) 20·00 (8·20) 0·53 (0·08)
46·40 (11·82*) 37·26 (7·47*) 53·81 (15·02*) 28·50 (6·86) 0·50 (0·04)
20 mg kg–1 58·16 (16·23) 29·32 (2·17) 14·62 (11·83) 28·00 (3·00) 1·24 (0·18)
20 mg kg–1 + FBZ 55·74 (17·51) 36·58 (9·84) 27·11 (14·72) 20·33 (5·74) 0·88 (0·06*)
* Significant difference (P ≤ 0·05) between each treatment of netobimin alone and with fenbendazole
sulphoxide by two enzyme systems, flavine monooxygenase enzyme system (FMO) and cytochrome P450. Albendazole sulphoxide has two enantiomers (–) and (+), that are produced from the prochiral thioether albendazole and can be separated by HPLC. In sheep, 86 per cent of the plasma AUC is represented by enantiomer albendazole sulphoxide (+), which is generated through the activity of the FMO system (Delatour et al 1991). There is substrate competition between fenbendazole and albendazole for the FMO pathway. Lacey et al (1994) suggested that Cmax/AUC is a better estimation than Cmax as indirect measure of rate of drug absorption in comparative pharmacokinetic studies. So, the decrease of rate of albendazole absorption, that we have obtained, estimated as Cmax/AUC of albendazole sulphoxide, indicates that fenbendazole is delaying the biotransformation rate from albendazole to its metabolite albendazole sulphoxide and as a consequence causing an extended time of albendazole sulphoxide formation. A significant increase of the MRT of sulphoxide was produced. Furthermore, a significantly longer half-life of the terminal exponent (T1/2) was observed when fenbendazole was co-administered
with netobimin and this could influence the increase of AUC0-∞ and MRT. This observation would suggest a saturation of the sulfonation pathway by both anthelmintics because there was no evidence of any change of the albendazole sulphone/albendazole sulphoxide ratio when the AUC0-∞ of albendazole sulphoxide was increased (Table 1). The pharmacokinetic parameters for albendazole sulphone is included in Table 2. Two pharmacokinetic features could help to improve the bioavailability of albendazole sulfoxide. First, albendazole sulphoxide has been shown to be efficiently reduced back to albendazole in the rumen of sheep (Lanusse et al 1992) and fenbendazole is found in the plasma for a longer time after administration than albendazole in sheep (Lanusse et al 1995) which would result in a longer competitive inhibition effect. The lack of effect of FBZ on the higher dose of netobimin could be because the concentration of netobimin is much higher than the one of FBZ and there is no competition at level of sustrate. Similar results have been obtained by Hennessy et al (1985). They observed that the highest increase in the AUC appears when equal dosages of parbendazole and oxfendazole were administered.
Bioavailavility of albendazole sulphoxide in sheep. The efficacy of albendazole and netobimin may be improved by co-administration of metabolic inhibitors which act mainly by increasing the plasma concentration profiles. The methimazole inhibits the FMO system and it has been shown to potentiate netobimin pharmacokinetic profile in sheep (Lanusse and Prichard 1992). Also, the interaction of inhibitors of cytochrome P450 such as cimetidine and piperonyl butoxide has pharmacokinetic implications on relation to albendazole (Wen et al 1994) and fenbendazole (Benchaoui and McKellar 1996). The co-administration of other benzimidazole drugs has shown to potentiate the anthelmintic activity. So, parbendazole increases the disposition of oxfendazole (Hennessy et al 1985, 1992). Fenbendazole coadministered with netobimin also has been used to improve the treatment of secondary hydatid cysts in gerbils (García et al 1997). In conclusion, the co-administration of fenbendazole (1·1 mg kg–1) with netobimin increased the pharmacokinetic disposition of the active metabolite in sheep which may enhance its efficacy against helminthosis.
ACKNOWLEDGEMENTS This work was supported by Junta de Castilla y León (22/12/95).
REFERENCES BENCHAOUI, H.A. & MCKELLAR, Q.A. (1996) Interaction between fenbendazole and piperonyl butoxide: pharmacokinetic and pharmacodynamic implications. Journal of Pharmacy and Pharmacology 48, 753–759. DELATOUR, P., CURE, M.C., BENOIT, E. & GARNIER F. (1986) Netobimin (Totabin-SCH): preliminary investigations on metabolism and pharmacology. Journal of Veterinary Pharmacology and TherapheutiCs 9, 230–234. DELATOUR, P., BENOIT, E., CAUDE, M. & TAMBUTE, A. (1991) Species differences in the generation of the chiral sulfoxide metabolite of albendazole in sheep and rats. Chirality 2, 156–160.
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Accepted February 8, 1999