SHORT COMMUNICATION J . vet. Phamcol . Therap. 16,237-240, 1993.

Pharmacokinetics of albendazole, albendazole sulfoxide and netobimin in goats H. A. BENCHAOUI , E. W. S C O T T & Q. A . MCKELLAR Department of Veterinary Pharmacology, University of Glasgow Veterinary School, Bearsden Road, Bearsden, Glasgow

Albendazole, albendazole sulfoxide and neto- bimin are three related broad spectrum anthelmintics used widely for the treatment and control of helminthiases in sheep and cattle (Campbell, 1990). In goats, the efficacy of albendazole has been assessed against Muellerius capillaris (Helle, 1986) and Fasciola gigantzca (Misra et al., 1989). Recently, netobi- min has been shown to be efficacious against combined infection with Muellerius capillaris and benzimidazole resistant gastrointestinal nematodes when administered orally at 7.5 mg/kg on three successive occasions or at 10 mg/kg on two successive occasions (Cabaret, 1991). However, dosage regimens and treat- ment frequencies are still not well established for the optimal efficacy of these anthelmintics in goats.

The pharmacokinetic behaviour of alben- dazole (Marriner & Bogan, 1980; Hennessy et al., 1989; Prichard et al., 1985), its synthetic metabolite albendazole sulfoxide (Tiberghien & Bogan, 1987) and its precursor netobimin (Delatour et al., 1986; Steel & Hennessy, 1987; Steel et al., 1985; Lanusse 8c Prichard, 1990; Lanusse et al., 1990; Lanusse et al., 1991) are well documented in sheep and cattle but little information is available in goats (Delatour el al., 199 1). Plasma concentrations achieved by the active moieties and their persistence in plasma are of primary importance for the anthelmintic efficacy of benzimidazole drugs (Prichard et al., 1978).

The purpose of the present study was to investigate the fate of albendazole, albenda- zole sulfoxide and netobimin, in the plasma of goats.

Seven mixed breed healthy goats weighing 11.5 to 30.0 kg at the beginning of the experiment were randomly allocated to two

groups of two animals and one group of three animals and maintained indoors with hay and water provided ad libitum. The groups were administered albendazole (Valbazen 2.5%; Smith Kline Animal Health Ltd.), albendazole sulfoxide (Albendazole oxide 2.5%; Rycovet Ltd.) or netobimin (Hapadex 2.5%; Kirby Warrick Ltd.) and the experiment was re- peated on three occasions with a 1-2 week wash out period such that all goats received each drug in a three way crossover design.

The three drug products, albendazole, albendazole sulfoxide and netobimin, were given by the oral route at a dose rate of 7.5 mg/kg bodyweight which corresponds to 2.83 X 2.66 x and 1.78 X lop5 moles of albendazole sulfoxide (ABSO), respectively. For each phase, blood samples were taken prior to treatment and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 32, 48, 72 and 96 h after dosing. Plasma was removed after centrifugation and stored at -20°C until analysed by high per- formance liquid chromatography (HPLC).

Samples collected were processed by solid phase extraction using Sep Pak C18 cartridges (Waters Chromatography Division, Milfort, USA) according to the method developed by Allan et al. (1980) and modified by Hennessy et al. (1985). The HPLC conditions for the detection of albendazole and its sulfoxide and sulfone metabolites, were as described by Marriner and Bogan (1980). The mobile phase used for the measurement of netobimin was a solvent mixture of methano1:water (47:53) to which was added 0.77 ml of per- cloric acid (1.1 % wlv) per 100 ml of solvent, running at a flow rate of 1.6 ml/min. The UV detector was set at 347. The limit of detection was below 0.04 pglml.

Following its oral administration netobimin

237

238 H. A. Benchaoui et al.

was not detectable in plasma at any time; neither was its sulfide metabolite albendazole. The latter was also below the limit of analytical detection when given as the parent drug. The plasma concentration versus time profiles of the t w o major metabolites albendazole sulfox- ide (ABSO) and albendazole sulfone (ABS02) for the three anthelniinthic preparations are shown in Fig. 1. ’l’here were no significant differences in the kinetic parameters of the active metabolite ABSO when albendazole and albendazole sulfoxide were administered at similar dose rates. However, after adminis- tration of netobimin at 7.5 mg/kg, the area under the plasma concentration-time curve (AUC) and the mean maximum concentration (Cn,ax) for ABSO were significantly lower

3 1 - - E m . - q 2 .. L c U c 0

U 1 . - a

0 0 4 8 1 2 1 8 2 0 24 2 8 3 2 3 6 4 0 4 4 4 8

Tlma (h)

FIG. 1 . Albendazole sulfoxide (ABSO) and albenda- zole sulfone (ABS02) after oral administration of albendazole, albendazole sulfoxide and netobimin at 7.5 mg/kg. -A- , ABSO after albendazole; -A-, A B S 0 2 after albendazole; 4-, ABSO after albenda- zole sulfoxide; -0-, ABS02 after albendazole sulf- oxide; -0- , ABSO after netobimin; -0-, ABSOp after netobimin.

when compared to the two other compounds (Table I). The AUC ratios of ABSO,/ABSO were 0.55, 0.51 and 0.56 following’adminis- tration of albenclazoie, albendazole sulfoxide and netobimin, respectively. The estimate of AUIC was based on plasma concentration^ from time of drug administration t o 48 h after dosing. The time until maximum plasma concentrations (t,,,J of- ABSO were attained and the apparent elimination half-lives (t,,J were not significantly different.

The anthelmintic activity of netobimin is conditioned by its conversion into albenda- zole (Fig. 2). It consists of a reduction and a cyclization exerted by the gastrointestinal microflora (Delatour et al., 1986). This process seems to be accomplished before any absorp- tion of the prodrug occurs, which explains the non-detection of netobimin in the plasma. The absence of netobirnin from the plasma has also been reported in cattle following oral administration of netobimin at a 20 mg/kg dosage rate (Lanusse rt ul., 1991). The absence of albendazole in the blood collected from the jugular vein is reflective of the first-pass oxidation that this compound undergoes in the liver (Marriner & Bogan, 1980; Hennessy et at., 1989). Despite its greater water solubil- ity, albendazole sulfoxide did not have a significantly higher bioavailability when coni- pared to the parent compound. This finding is in agreement with previous observations in sheep and cattle where albendazole and alben- dazole sulfoxide proved bioequivalent (Tiber- ghien & Bogan, 1987).

The ratio AUC (ABS02)IAUC (ABSO) rang- ing between 0.51 and 0.56 for the three drug products is consistent with that reported by

TABLE I . Mean (+ SEM, n = 7) pharmacokinetic parameters for albendazole sulfoxide following oral administration of albendazole, albendazole sulfoxide and netobimin at a dose rate of 7.5 mg/kg body weight

Albendazole Albendazole sulfoxide Netobimin

C,nm (Fg/ml) 2.38 f 0.15 2.77 k 0.20 1.35 k 0.131 t,,, th) 11.43 t 0.57 11.43 5 0.57 10.86 i 0.74 AUC (pg.h/ml) 54.40 t 5.96 63.04 ? 7.15 29.76 2 3.14t ty2 (h) 9.04* 8.34* 8.09*

*Harmonic mean; t P < 0.05 (Mann-Whitney U-test)

Albendazole and related drugs in goats 239

Delatour et u1. (1991), in goats after treatment with albendazole. In the same study, the authors have also demonstrated that the parameter AUC (ABS02)/AUC (ABSO), which reflects the hepatic sulfonating capacity, was greater in goats than in sheep.

In cattle, netobimin is recommended at the same dose rate as albendazole and albenda- zole sulfoxide (7.5 mg/kg). Since the mole- cular weight of the prodrug is higher than that of the sulfide o r sulfoxide metabolites (Fig. 2 ) , the dosage rate should be adjusted on the molar basis for bioequivalence. In goats, if the dose rate of 7.5 mgikg is adopted for albendazole, the adequate equivalent dosage for netobimin would be 58.93% higher (i.e. 1 1.92 mg/kg).

Comparative studies have revealed consid- erable differences between ruminant species

,NH -CHzCH,S03H

(Gut microflora) 1 ALBBNDAZOLE

(mw=Z65.33)

(Liver) I 0 I I

( L i v e r ) 1 0 II

ALBENDAZOLESULFONE (mw=297.32)

FIG. 2. Biotransforrnation of netobimin

regarding the pharmacokinetics of anthelmin- tic drugs. Most of these studies emphasise the differences encountered between goats and sheep. I t has been reported that thiabenda- zole was metabolised faster in goats than in sheep (Weir & Bogan, 1985). Also in goats the AUC of the active sulfoxide metabolite after oral administration of oxfendazole was 58% smaller than in sheep (Bogan et al., 1987). This lower bioavailability may account for the poor efficacy reported for oxfendazole given t o goats at the dose rate recommended for sheep (Kettle et al., 1983). A similar observa- tion has been made by Gillham & Obendorf (1985) and Coles et al. (1989) to explain the poor efficacy of levamisole in goats. These differences extend to fasciolicide drugs. The AUC of clorsulon in goats after oral adminis- tration was 60% of that in sheep (Sundlof et ul., 1991) and closantel seemed to be more quickly eliminated in goats than in sheep (Hennessy, personal communication).

These observations suggest that it is neces- sary to evaluate the kinetic parameters sepa- rately for each species and that extrapolated data can be misleading in predicting adequate dosage regimens and withdrawal times.

ACKNOWLEDGMENTS

H. A. Benchaoui is in receipt of ajoint funded AlgeriadBritish government award. The assistance of P. Baxter is gratefully acknow- ledged.

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