Pharmacokinetic profiles of netobimin metabolites after oral administration of zwitterion and trisamine formulations of netobimin to cattle

Abstract

Pharmacokinetic profiles of the major metabolites of netobimin were investigated in calves after oral administration of the compound (20 mg/kg) as a zwitterion suspension and trisamine salt solution in a two-way cross-over design. Blood samples were taken serially over a 72-h period and plasma was analysed by HPLC for netobimin (NTB) and its metabolites, including albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2). NTB was occasionally detected in plasma between 0.5 and 1.0 h post-treatment. ABZ was not detectable at any time. ABZSO was detected from 0.5-0.75 h up to 32 h post-administration, with a Cmax for the zwitterion suspension of 1.21 +/- 0.13 micrograms/ml and AUC of 18.55 +/- 1.45 micrograms.h/ml, respectively, which were significantly higher (P less than 0.01) than the Cmax (0.67 +/- 0.12 micrograms/ml) and AUC (8.57 +/- 0.91 micrograms.h/ml) for the trisamine solution. ABZSO2 was detected in plasma between 0.75 and 48 h post-administration. The zwitterion suspension resulted in a Cmax (2.91 +/- 0.10 micrograms/ml) and AUC (51.67 +/- 1.95 micrograms.h/ml) for ABZSO2, which were significantly higher (P less than 0.01) than those obtained for the trisamine solution (Cmax = 1.67 +/- 0.11 micrograms/ml and AUC = 22.77 +/- 1.09 micrograms.h/ml). The ratio of AUC for ABZSO2/ABZSO was 2.92 +/- 0.26 (zwitterion) and 2.80 +/- 0.20 (trisamine). The MRT for ABZSO2 was significantly longer (P less than 0.01) after treatment with the zwitterion suspension than after treatment with the trisamine solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioconversion of netobimin pro-drug by gastrointestinal fluids of ruminants

“…These in vitro results confirm the previous in vivo pharmacokinetic findings in cattle, which showed that ABZSO and ABZSQz the main metabolites found in plasma, were 2-fold more bioavailable after administration of a zwitterion suspension than after treatment with a trisarnine solution of NTB (5). pH modification of the zwitterion formulation resulted in decreased NTB consumption and lower production of its cyclised metabolites.…”

“…This evidence and the extensive metabolism of the compound by ruminal and ileal fluids reported in this article indicate that the gastrointestinal tract may be the only site where bioactivation of NTB takes place. This correlates well with the significantly lower proftles of ABZ metabolites obtained following parenteral administration of NTB in sheep and cattle, compared with those obtained after oral or intraruminal administration (4,5). The efficiency of conversion of parenterally administered NTB may depend on the amount of pro-drug that reaches the digestive tract by plasrnagastrointestinal tract exchange or bile.…”

“…Both route of administration and formulation have been shown to greatly influence the rate of NTB bioconversion and the resultant bioavailability and plasma disposition of its main metabolites in sheep and cattle (4,5). Although bioequivalent following parenteral treatment (6) the zwitterion and trisamine salt formulations of NTB were not bioequivalent after oral administration to cattle (5). Differences in the rate of conversion of NTB into its metabolites may contribute to these differences between formulations.…”

“…The gastrointestinal microflora have been proposed as the main site for NTB conversion into its anthelmintically active ABZ metabolites (3,5). Both route of administration and formulation have been shown to greatly influence the rate of NTB bioconversion and the resultant bioavailability and plasma disposition of its main metabolites in sheep and cattle (4,5). Although bioequivalent following parenteral treatment (6) the zwitterion and trisamine salt formulations of NTB were not bioequivalent after oral administration to cattle (5).…”

Methimazole increases the plasma concentrations of the albendazole metabolites of netobimin in sheep

“…Blood samples (10 ml) were taken from the jugular vein in vacutainer tubes with sodium heparin (Becton Dickinson, Mississauga, Ont., Canada) prior to the treatments and at 0.5, 1,2,4,6,8,10,12,18,24,30,36,48,72,96, and 120 h post-treatment. Plasma was separated by centrifugation at 3000 rev min-' for 15 min, placed into plrstic vials, and frozen at -20" until analysed.…”