Fumagillin, a new P‐glycoprotein‐interfering agent able to modulate moxidectin efflux in rat hepatocytes¹

Abstract

We have tested the ability of two compounds licensed in veterinary medicine: fumagillin and diminazene diaceturate to increase intracellular moxidectin quantity in rat hepatocytes. These compounds significantly increased the quantity of 14C-moxidectin (expressed as area under the time curve concentrations) in cultured rat hepatocytes by 44% and 65% for diminazene and fumagillin treatments respectively. In addition, we have tested these drugs for their interference with P-glycoprotein (P-gp) function in porcine kidney epithelial cells transfected with murine mdr1a (Mdr1a-LLCPK1). We examined the intracellular accumulation of rhodamine 123 (Rho 123) as a functional test to evaluate the effects of these two drugs on P-gp activity. In this model, only fumagillin led to a marked intracellular accumulation of Rho 123. After transforming the data to express the results as a percentage of the accumulation in the presence of the P-gp inhibitor valspodar (VSP), the maximal Rho 123 accumulation was 47% of that with VSP for 100 microm fumagillin. The EC50, the concentration needed to determine 50% of the maximal effect was 34 microm. Fumagillin interacts with P-gp function and appears as a promising compound among registered drugs available, which may optimize the therapeutic use of macrocyclic lactones (MLs).

Interaction of Macrocyclic Lactones with the Multidrug Transporters: The Bases of the Pharmacokinetics of Lipid-Like Drugs

“…More recently, the use of ketoconazole in dogs [118] or sheep [119] and itraconazole in sheep [120] or rat [82], in combination with ivermectin, doubled the area under the plasma concentration-time curve compared with ivermectin alone. Recently, another compound fumagillin was also shown to increase the ML bioavailability likely through inhibition of P-gp [121]. Lowering the therapeutic dose of ivermectin could also be considered when it is co-administered with such MDR transport inhibitors.…”

Macrocyclic Lactones and Cellular Transport-Related Drug Interactions: A Perspective from In Vitro Assays to Nematode Control in the Field

“…The interaction of MXD with the ABC transporters was demonstrated in cultured rat hepatocytes. Ketoconazole, quercetin and fumagillin increased the quantity of 14C-moxidectin in hepatocytes [80,81]. It has been recently shown that affinity by P-gp may differ among different ML molecules [23].…”

Flavonoid-Mediated Modulation of CYP3A Enzyme and P-Glycoprotein Transporter: Potential Effects on Bioavailability and Disposition of Tyrosine Kinase Inhibitors

“…These experiments include in vitro analyses of the effects of flavonoids on the intracellular accumulation of P-gp substrates using P-gp-overexpressing cells and a variety of clinical and animal model studies, especially involving P-gp knockout animals [37]. For example, concomitant administration of quercetin increased moxidectin oral bioavailability in lambs [72]; oral bioavailability of quinine was increased by naringin [73]; cyclosporine by baicalein and its aglycone [74]; and paclitaxel by flavones in rats [75]. Similarly, quercetin increased the oral bioavailability of paclitaxel and tamoxifen in rats [76,77] and digoxin in pigs, which results in high toxicity [78].…”