In vitro and in vivo assessment of the interaction between danofloxacin and ivermectina in sheep.

BALLENT, M.; LIFSCHITZ, A.; VIRKEL, G.; SALLOVITZ, J.; MATÉ, L.; LANUSSE, C.

Córdoba

Congreso; Reunión Internacional de Ciencias Farmacéuticas; 2010

Introduction: A potential drug interaction refers to the possibility that one drug may alter the intensity of the pharmacological effects of another drug given concurrently (Nies and Spielberg, 1996). Although  less frequent compared to drug interactions involving the cythocrome P450 system, clinically significant ATP binding cassette (ABC) transporter-mediated drug interactions have been reported (Lin, 2007). ABC transporters are physiologically located in tissues involved in the pharmacokinetic processes such as the brain-blood barrier, luminal surface of hepatocytes and ducts cells, kidney tubules and enterocytes (Lin, 2003). Concomitant administration of multiple drugs is often used in current veterinary practice, which may drastically induce changes on the disposition kinetics and pharmacological activity of different therapeutically used drugs. The aim of the current trial was to evaluate the pharmacokinetic disposition of an antimicrobial drug (danofloxacin) and an antiparasitic compound (ivermectin) given either separately or co-administered to sheep. To further understand the basis of their kinetic interaction, complementary in vitro assays with the Ussing Chamber system were carried out. Matherial and methods: Corriedale sheep (in vivo experiment) received ivermectin (IVM) (0.2 mg/kg) by subcutaneous (s.c.) route (Group A). Group B received danofloxacin (DFX) by s.c. route (6 mg/Kg, twice every 48 h) and Group C received the co-administration of IVM+DFX, both administered at the same dose rate. Jugular blood samples were collected and the IVM and DFX concentrations were analyzed by HPLC using fluorescence detection. Additionally, the effect of IVM and DFX on Rhodamine 123 (Rho 123) intestinal transport was estudied in difussion chambers. The ileum segment of sheep intestine was opened along the mesenteric border and then partially stripped from underlying muscle layers. Resulting flat sheets of gut mucosa were mounted into Ussing chambers. Rho 123 (5 µM) was added to both mucosal (M) and serosal (S) sides either alone or with IVM (25 µM) and DFX (25 µM), used as P-glycoprotein (P-gp) modulators. Buffer samples were taken between 30 and 240 min for determination of drug flux across the mucosal and serosal membranes. The Rho 123 concentrations were measured by spectrofluorometric detection and the apparent permeability coefficients, per unit of membrane surface area (Peff) (cm/s), were estimated.   Results: No significant changes were observed in the IVM disposition after its co-administration with DFX. However, the IVM presence affected the DFX plasma disposition in sheep. IVM enhanced the DFX plasma availability (between 32 and 35 %) (P< 0.05) and prolonged its elimination half-life (between 40 and 52 %) (P< 0.05) in co-administered group. The efflux transport of Rho 123 in sheep intestine mounted in the Ussing chamber system was significant decreased in the presence of IVM. The efflux coefficient (PeffS-M/PeffM-S) decreased from 6.49 (Rho 123 alone) to 1.12 (Rho 123 + IVM) (P<0.05). However no significant differences were observed in the efflux coefficient in the presence of DFX (PeffS-M/PeffM-S= 5.52). Discussion: IVM affects the disposition kinetics of DFX in sheep. IVM is a recognised P-gp inhibitor (Schinkel et al., 1994). The Ussing Chamber assay corroborated the inhibition of the P-gp-mediated intestinal secretion of Rho 123. However, DFX did not modified the Rho 123 intestinal secretion. The fluoroquinolone antibacterials have been reported as substrates of different ABC transporters. IVM is also a weak inhibitor of the breast cancer resistance protein (BCRP) (Muenster et al., 2008). Therefore, a drug to drug interaction with BCRP should not be ruled out in the in vivo changes to the kinetics of DFX co-administered with IVM. References: Lin, JH. (2007). Expert Opin. Drug Metab Toxicol. 3: 81-92. Lin, JH. (2003). Adv. Drug Deliv. Rev. 55:53-81. Muenter U. et al. (2008). Pharm. Res. 25:2320-2326. Nies, AS and Spielberg, SP. (1996). Principles of Theraputics, 9th Ed. p. 43-61. Schinkel, AH. et al. (1994). Cell. 20: 491-502.