The effect of feed quality on the kinetic disposition of orally administered triclabendazole in sheep

THE EFFECT OF FEED QUALITY ON THE KINETIC DISPOSITION OF ORALLY ADMINISTERED

TRICLABENDAZOLE IN SHEEP

M. OUKESSOU* AND Z. SOUHAILI

Department of Physiology and Therapeutics, Hassan II Agronomic and Veterinary Institute, 6202, Rabat, Morocco

*Correspondence

ABSTRACT

Oukessou, M. and Souhaili, Z., 1998. The e¡ect of feed quality on the kinetic disposition of orally administered triclabendazole in sheep.Veterinary Research Communications,22(4), 257^263

The e¡ect of two qualities of feed on the kinetic disposition of triclabendazole (TCBZ) metabolites was investigated in sheep (n= 4) following oral administration of TCBZ at 10 mg/kg body weight. The same sheep were given sequentially two qualitatively di¡erent diets: a low-quality (LQ) diet based on wheat strawad libitum, and a high-quality (HQ) diet based on barley+alfalfa. The triclabendazole sulphoxide (TCBZSO) and triclabendazole sulphone (TCBZSO2) concentrations were determined in blood samples taken serially from the jugular vein between 5 min and 9 days after TCBZ administration.

The parent drug TCBZ was not detected in any of the samples. The quality of feed a¡ected the kinetics of both TCBZ metabolites. The rate of appearance (TlagandTmax) in the jugular blood was slower and the formed amount (AUC) of TCBZSO was slightly higher when the sheep were on the LQ diet (Tlag= 7.74 h; Tmax= 27.91 h; AUC = 1042 mg.h/ml) than when they were o¡ered the HQ diet (Tlag= 1.90 h;Tmax= 16.01 h; AUC = 832.4mg.h/ml). The MRT of TCBZSO was about 40% longer with the LQ diet than with the HQ diet. Similarly, the rate of appearance of TCBZSO2 in plasma of sheep was slower when they were on the LQ diet than when they were on the HQ diet, suggesting an impairment of the hepatic enzymatic activity involved in the oxidation of TCBZSO to TCBZSO2. Keywords:anthelmintics,Fasciola, nutrition, pharmacokinetics, sheep, triclabendazole

Abbreviations:AUC, area under the plasma concentration^time curve; BZ, benzimidazoles;Cmax, peak plasma concentration; HQ, high-quality of feed; LQ, low-quality of feed; MRT, mean residence time;

TCBZ, triclabendazole; TCBZSO, triclabendazole sulphoxide; TCBZSO2, triclabendazole sulphone;

T¹₂k(a), half-life of formation;T¹₂k(10), half-life of elimination;Tlag, lag time;Tmax, time to reachCmax

INTRODUCTION

Oral administration is the most common method used to control endoparasites in livestock because it is easy to use and because of the lack of parenteral formulations of the benzimidazole (BZ) anthelmintics. However, many physiological factors (Prichard, 1985) and farming practices can interact with the oral bioavailability of anthelmintics and thereby change their e¤cacy. Among such factors, those of a dietary nature are well documented. Changes in the level of feed intake were reported to in£uence markedly the oral bioavailability of various anthelmintic agents, including oxfendazole (Ali and Hennessey, 1995a,b), ivermectin (Ali and Hennessey, 1996) and albendazole (Sanchez et al., 1996).

257

Under Moroccan husbandry conditions, sheep are almost exclusively extensively reared and they are therefore subjected to qualitative and quantitative £uctuations in feed supply throughout the year. Feeds are, generally, abundant and of high quality during spring and early summer, but become scarce and of low quality from late summer and throughout the autumn, when the pastures are primarily stubble.

Flukicidal drugs are generally given in the autumn and winter although infection with Fasciola is possible throughout the year.

The aim of the present study was to compare the e¡ect of two qualities (high and low) of feed on the kinetic disposition of triclabendazole (TCBZ), a potent £ukicidal BZ commonly used in livestock.

MATERIALS AND METHODS Experimental animals

Four adult Timahdit ewes in good health and weighing 27.5 to 43.5 kg were used. The Timahdit breed of sheep is native to the middle-Atlas region in the centre of Morocco, where they are reared exclusively in an extensive manner. The ewes were housed in a 30 m

²

room and were treated orally with oxfendazole (5 mg/kg) against endoparasites 1 month before the experiment. The experiment was carried out in two phases. In phase 1, the animals were o¡ered a low-quality (LQ) diet based on wheat straw ad libitum for at least 8 weeks before they were given TCBZ. In phase 2, the animals were fed on a high-quality (HQ) diet based on barley+alfalfa (400+400 g/day per animal) for at least 5 weeks before they were given TCBZ again. Water was provided ad libitum during both phases of the experiment. In each case, the animals were weighed just before the drug was administered.

Drug administration and blood sampling

Triclabendazole (Fasinex 5% suspension; Ciba-Geigy Animal Health, Basle, Switzer- land) was given orally to each ewe at 10 mg/kg body weight using a syringe placed on the tongue. The animals had free access to feed before and immediately after the TCBZ was given. Blood samples (4^5 ml) were collected by jugular venepuncture into heparinized vials at time 0 (before) and at 5, 10 and 30 min and at 1, 2, 4, 8, 10 and 24 h, and thereafter daily up to 9 days after administration of the TCBZ. Plasma was separated by centrifugation (3000g) within 10 min after sampling and stored at ^208C until analysis.

Analytical methods

The concentrations of TCBZ and its metabolites (TCBZSO and TCBZSO

₂

) in the

plasma were determined by high-performance liquid chromatography (HPLC) as

described previously (Bull and Shume, 1987; Oukessou et al., 1991). This method allows simultaneous quanti¢cation of TCBZ, TCBZSO and TCBZSO

2

. The limit of quanti¢cation was 0.05 mg/ml for both TCBZ and its metabolites, with an inter-assay coe¤cient of variation of 3.2^4.6%.

Data analysis

The individual data were analysed with a nonlinear least-squares regression program (Yamaoka et al., 1981). The plasma concentrations of TCBZSO and TCBZSO

2

were

¢tted to a monoexponential equation. The relevant pharmacokinetic parameters of the two analytes were calculated according to standard equations (Gibaldi and Perrier, 1982). The area under the plasma concentration^time curve (AUC) and the mean residence time (MRT) were calculated using the trapezoidal rule, with extrapolation to in¢nity.

The pharmacokinetic parameters for the two diets were compared using Student's t- test for paired data at a signi¢cance level of p40.05. Data are reported as mean+SD.

RESULTS

As was expected, the dietary quality resulted in di¡erences in the live weights of the sheep. The animals' live weights were 32.6+3.4 kg during the study period on the LQ diet compared with 38.9+3.1 kg when they were on the HQ diet. This corresponded to an average weight loss of 6.3+3.3 kg during the LQ dietary period, and indicates the poor nutritional status of animals when receiving only wheat straw ad libitum.

The parent TCBZ was not detected in any of the plasma samples during either period of the study. The mean plasma concentration^time curves for TCBZSO and TCBZSO

₂

are shown in Figure 1, with the corresponding pro¢les given in Table I.

Apparent di¡erences were observed in the mean plasma pro¢les and pharmacokinetic parameters of both TCBZ metabolites according to diet. However, owing to great individual £uctuations, most of the observed di¡erences were not statistically signi¢cant.

DISCUSSION

The e¡ect of dietary variations, especially of the level of feed intake, on the kinetic disposition and e¤cacy of anthelmintics in sheep has been investigated for oxfendazole (Ali and Hennessy, 1995a,b) and ivermectin (Ali and Hennessey, 1996). These authors' studies showed that both the bioavailability and the e¤cacy of these drugs increased signi¢cantly in animals on a low (400 g/day) as compared with those on a high (800 g/

day) level of feed intake.

Figure 1. Mean plasma concentrations of TCBZSO and TCBZSO

2

after a single dose of TCBZ (10 mg/kg) in four sheep o¡ered high-quality (HQ) or low-quality (LQ) diets

TABLE I

Selected pharmacokinetic parameters (mean+SD) of triclabendazole metabolites following oral triclabendazole administration (10 mg/kg) in four sheep o¡ered high (HQ) or low (LQ) qualities of feed

TCBZSO TCBZSO

2

Parameters HQ LQ HQ LQ

T¹₂k(a)

(h) 6.07

^a+4.25

10.83

^a+6.34

19.98

^a+9.30

22.02

^a+4.69 T¹_2k(10)

(h) 19.20

^a+2.09

21.98

^a+2.90

29.92

^a+5.26

26.01

^a+4.44 T_lag

(h) 1.90

^a+0.58

7.74

^b+0.81

4.99

^a+1.45

19.68

^b+1.22

MRT (h) 39.49

^a+7.44

56.66

^b+6.88

78.79

^a+4.12

85.11

^a+7.65 T_max

(h) 16.01

^a+6.54

27.91

^b+7.39

38.06

^a+9.19

53.91

^b+4.92 C_max

(mg/ml) 17.42

^a+4.61

16.58

^a+7.46

13.54

^a+2.32

10.44

^a+4.54

AUC ((mg/h)/ml) 832.4

^a +285.6 1042.0^a +590.7

1301.7

^a +339.7 984.4^a +541.0

AUC

_TCBZSO2

/AUC

_TCBZSO

1.63

^a+0.38

0.97

^a+0.22

a,bFor each parameter and metabolite, means with di¡ering superscripts were di¡erent atp40.05 between the two qualities of feed

As the parent TCBZ was not detected in any of the samples during either experimental period, it is clear that TCBZ was rapidly and completely metabolized in the liver. The longer TCBZSO lag time and the later T

max

in sheep on the LQ compared to the HQ diets suggests that the parent TCBZ was delivered more slowly to the liver, and/or that the hepatic oxidative activity was reduced when the sheep were on the LQ diet. The quality and ¢bre content of feed are known to in£uence the out£ow of digesta from the forestomachs in various ruminant species (Church, 1979). The mean residence time of particles in the reticulo-rumen is markedly increased in sheep fed on a low-quality,

¢brous diet (Lechner-Doll et al., 1990). Since the ¢bre content is higher in wheat straw than in alfalfa and barley (National Research Council, 1985), the mean residence time of TCBZ in the reticulo-rumen was probably longer in the sheep on the LQ as compared to the HQ diets, which may explain the above di¡erences in the delay in the appearance of TCBZSO in the jugular blood. However, impairment of hepatic oxidative function in sheep on the LQ diet cannot be excluded, since this function, as assessed by antipyrine clearance, was reported to be slower in children with protein^

energy malnutrition (Narang et al., 1979). Such an e¡ect may be implicated in the signi¢cantly slower rate of TCBZSO

2

formation in the sheep o¡ered LQ diets.

Conversely, the earlier appearance of TCBZSO in the plasma of sheep on the HQ diet may indicate that some of the TCBZ had bypassed the reticulo-rumen through closure of the oesophageal groove, although this is unlikely to have occurred in all the four sheep on the HQ diet.

The elimination half-life of TCBZSO was not altered, although the mean residence time (MRT) was about 40% longer in the sheep fed on the LQ diet than when they received the HQ diet. This increase in the MRT may be mainly related to delayed absorption of TCBZ. However, to determine the true value of the elimination half-life, the TCBZSO should be injected intravenously.

TCBZSO is irreversibly oxidized to TCBZSO

2

, an anthelmintically inactive metabo- lite. As with other BZ, such as fenbendazole, this metabolic step is slower and depends on the cytochrome P450 system (Lanusse and Prichard, 1993). The e¡ects of feed restriction on drug metabolism and the associated enzymes have been described in human beings and laboratory animals (Campbell, 1977; Krishnaswamy, 1989). These authors reported that protein^energy undernutrition markedly decreases the activity of the hepatic drug-metabolizing enzymes. There is no doubt that the sheep o¡ered the LQ diet were protein^energy undernourished, but it is not known whether this undernutrition had induced an alteration in drug-metabolizing enzymes, speci¢cally of the cytochrome P450 system. The low TCBZSO

2

and the high TCBZSO AUCs as well as the low ratio of the TCBZSO

2

AUC to the TCBZSO AUC in sheep fed on the LQ diet, as compared to those o¡ered the HQ diet, provides some evidence for relatively slow formation of TCBZSO

2

and for possible impairment of the hepatic oxidative function in the sheep o¡ered the LQ diet.

The value of pharmacokinetic studies in assessing the e¤cacy of an anthelmintic is

based on the assumption that the plasma concentration pro¢le of the anthelmintic

and/or its active metabolites relates to the concentration of the active moiety at the site

of action (Baggot and McKellar, 1994). This relationship, accepted for various other

anthelmintic BZ, appears even more valid for TCBZSO, because the site of action is

outwith the digestive tract in the highly vascular liver, and the target parasites (Fasciola spp.) are haematophagous. In contrast to antimicrobial drugs, the concept of the minimum e¡ective plasma concentration of the active moiety is not commonly used for BZ anthelmintics. However, it has been shown for TCBZ that concentrations of 10^25 mmol/L (3.75^9.37 mg/ml) markedly inhibit the motility of Fasciola hepatica in vitro, and this parasite is more sensitive to TCBZSO than to the parent TCBZ, given an exposure time of at least 24 h (Bennet and Ko«bler, 1987). Based on these data, and taking into account the relatively high plasma concentrations and longer mean residence time for the TCBZSO in the sheep fed on the LQ diet, compared to those on the HQ diet, it may be anticipated that a poorer quality of feed will enhance the

£ukicidal activity of TCBZ. This is supported by the fact that the TCBZSO plasma concentration remained above 4 mg/ml for about 87 and 68 h, respectively, in sheep o¡ered LQ and HQ diets.

In conclusion, the results of this study showed that the disposition kinetics of TCBZ is a¡ected by the quality of the feed and con¢rm those reported previously for other anthelmintic drugs.

ACKNOWLEDGMENTS

This study was supported by the International Foundation for Science (grant no. 1110/

3). We thank Mr Ablouh and Mrs Alassal for technical assistance.

REFERENCES

Ali, D.N. and Hennessey, D.R., 1995a. The e¡ect of level of feed intake on pharmacokinetic disposition of oxfendazole in sheep.International Journal for Parasitology,25, 63^70

Ali, D.N. and Hennessey, D.R., 1995b. the e¡ect of reduced feed intake on the e¤cacy of oxfendazole against benzimidazole resistant Haemonchus contortus andTrichostrongylus colubriformis in sheep.

International Journal for Parasitology,25, 71^75

Ali, D.N. and Hennessey, D.R., 1996. The e¡ect of level of feed intake on the pharmacokinetic disposition and e¤cacy of ivermectin in sheep.Journal of Veterinary Pharmacology and Therapeutics,19, 89^94 Baggot, J.D. and McKellar, Q.A., 1994. The absorption, distribution and elimination of anthelmintic

drugs: the role of pharmacokinetics.Journal of Veterinary Pharmacology and Therapeutics,17, 409^419 Bennet, J.L. and Ko«bler, P., 1987. Fasciola hepatica: actionin vitroof triclabendazole on immature and

adult stage.Experimental Parasitology,63, 49^57

Bull, M.S. and Shume, G.R.E., 1987. A rapid high-performance liquid chromatographic procedure for the determination of triclabendazole and its metabolites in sheep plasma.Journal of Pharmaceutical and Biomedical Analysis,5, 527^531

Campbell, T.C., 1977. Nutrition and drug metabolizing enzymes.Clinical Pharmacology and Therapeutics, 22, 699^706

Church, D.C., 1979.Digestive Physiology and Nutrition of Ruminants, Vol. 1: Digestive Physiology, (O & B Books, Corvallis, OR, USA)

Gibaldi, M. and Perrier, D., 1982.Pharmacokinetics, 2nd edn, (Marcel Dekker, New York)

Krishnaswamy, K., 1989. Drug metabolism and pharmacokinetics in malnourished children. Clinical Pharmacokinetics,17(supplement 1), 68^88

Lanusse, C.E. and Prichard, R.K., 1993. Clinical pharmacokinetics and metabolism of benzimidazole anthelmintics in ruminants.Drug Metabolism Review,25, 235^279

Lechner-Doll, M., Rutagwenda, T., Schwartz, H.J., Schultka, W. and Engelhardt, W.v., 1990. Seasonal changes of ingesta mean residence time and forestomach £uid volume in indigenous camels, cattle,

sheep and goats grazing a thornbush savannah pasture in Kenya. Journal of Agricultural Science, Cambridge,15, 409^420

Narang, R.K., Mehtas, S. and Mathur, V.S., 1979. Pharmacokinetics study of antipyrine in malnourished children.American Journal of Nutrition,30, 1979^1982

National Research Council, 1985.Nutrient Requirements of Sheep, 6th edn, (National Academy Press, Washington DC)

Oukessou, M., Toutain, P.L., Galtier, P. and Alvinerie, M., 1991. E¨tude pharmacocine¨tique compare¨e du triclabendazole chez le mouton et le dromadaire.Revue d'E¨levage et de Me¨decine Ve¨te¨rinaire des Pays Tropicaux,44, 447^452

Prichard, R.K., 1985. Interaction of host physiology and e¤cacy of antiparasitic drugs.Veterinary Parasitology,18, 103^110

Sanchez, S.F., Alvarez, L.I. and Lanusse, C.E., 1996. Nutritional condition a¡ects the disposition kinetics of albendazole in cattle.Xenobiotica,26, 307^320

Yamaoka, K., Tnaigawara, Y., Nakagawa, T. and Uno, T., 1981. A pharmacokinetic analysis program (MULTI) for microcomputer.Journal of Pharmacobiodynamics,4, 879^889

(Accepted: 11 December 1997)