Assessment of the long-acting ivermectin formulation in sheep: Further insight into potential pharmacokinetic interactions.

The aim of the current study was to evaluate the in vivo pharmacokinetic of ivermectin (IVM) after the administration of a long-acting (LA) formulation to sheep and its impact on potential drug-drug interactions. The work included the evaluation of the comparative plasma profiles of IVM administered at a single therapeutic dose (200 µg/kg) and as LA formulation at 630 µg/kg. Additionally, IVM was measured in different gastrointestinal tissues at 15 days posttreatment with both IVM formulations. The impact of the long-lasting and enhanced IVM exposure on the disposition kinetics of abamectin (ABM) was also assessed. Plasma (IVM and ABM) and gastrointestinal (IVM) concentrations were analyzed by HPLC with fluorescent detection. In plasma, the calculated Cmax and AUC0-t values of the IVM-LA formulation were 1.47- and 3.35-fold higher compared with IVM 1% formulation, respectively. The T1/2ab and Tmax collected after administration of the LA formulation were 2- and 3.5-fold longer than those observed after administration of IVM 1% formulation, respectively. Significantly higher IVM concentrations were measured in the intestine mucosal tissues and luminal contents with the LA formulation, and in the liver, the increase was 7-fold higher than conventional formulation. There was no drug interaction between IVM and ABM after the single administration of ABM at 15 days post-administration of the IVM LA formulation. The characterization of the kinetic behavior of the LA formulation to sheep and its potential influence on drug-drug interactions is a further contribution to the field.

Assessment of liver slices for research on metabolic drug-drug interactions in cattle.

1. Precision-cut liver slices (PCLS) from food-producing animals have not been extensively used to study xenobiotic metabolism, and thus information on this field of research is sparse. 2. The aims of the present work were to further validate the technique of production and culture of bovine PCLS and to characterize the metabolic interaction between the anthelmintic albendazole (ABZ) and the flavin-monooxygenase (FMO) inhibitor methimazole (MTZ). 3. Nine steers were used as donors. PCLS were produced and incubated under two methods: a dynamic organ culture (DOC) incubator and a well-plate (WP) system. 4. Tissue viability, assessed through both structural and functional markers, was preserved throughout 12 h of incubation. ABZ was metabolized to its (+) and (-) albendazole sulfoxide stereoisomers (ABZSO) in bovine PCLS. The interaction between ABZ and MTZ resulted in a reduction (p < 0.001) in the rates of appearance of (+) ABZSO. Conversely, in presence of MTZ, the rates of appearance of (-) ABZSO increased under both systems (p < 0.05). 5. Both culture systems were suitable for assessing the interaction between ABZ and MTZ. 6. Overall, the results presented herein show that PCLS are a useful and reliable tool for short-term studies on metabolic drug-drug interactions in the bovine species.

Gene expression and enzyme function of two cytochrome P450 3A isoenzymes in rat and cattle precision cut liver slices.

1. Precision-cut liver slices are one of the in vitro models used in studies concerning xenobiotic metabolism. Sparse information on this field is actually available for cattle and other veterinary species. 2. The aim of the current work was to study the effect of dexamethasone (DEX) on the gene expression and function of CYP3A23 (in rat), CYP3A28 (in cattle) and the transcriptional factors involved in their regulation. 3. DEX (at 100 µM) up-regulated CYP3A23 mRNA (3.2-fold, p = 0.028) in rat liver slices after 12 h culture, whereas the gene expression profiles of transcriptional factors involved in CYP3A regulation were unaffected. A CYP3A-dependent enzyme activity (triacetyl-oleandomycin N-demethylase) increased 3.4-fold (p < 0.05) in rat liver slices cultured in the presence of DEX. 4. The protocol used for rat liver slices was used as reference to study the expression of a CYP3A isoenzyme in cattle liver slices. Oppositely, DEX did neither affect the gene expression profile of CYP3A28 nor the CYP3A activity tested in cattle liver slices. 5. The data reported here are a further contribution to demonstrate the usefulness of liver slices as an in vitro tool for studies on the expression and function of xenobiotic metabolizing enzymes in cattle and in other ruminant species.