P-gp/BCRP efflux and intestinal metabolism limit tigecycline exposure: Effects of elacridar and voriconazole in mice.

Tigecycline (TIG) exhibits poor oral bioavailability and brain distribution. Because bacterial efflux pumps that expel tetracyclines are homologous to mammalian P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), we investigated whether these transporters, along with TIG metabolism, affect TIG pharmacokinetics in mice. BALB/c and wild-type mice received TIG (10 mg/kg) intraperitoneally or orally alone, or in combination with the selective P-gp/BCRP inhibitor elacridar (ELA, 100 mg/kg p.o.) and/or the metabolic inhibitor voriconazole (VORI, 40 mg/kg i.p. or p.o.). One group also received a double TIG dose (20 mg/kg i.p.). Plasma and brain TIG concentrations were quantified via ultraperformance liquid chromatography coupled with tandem mass spectrometry. Differences in area under the curve (AUC) and Cmax were analyzed using Bayesian hierarchical models. In both mouse strains, oral ELA substantially increased the plasma AUCtlast (>1.8-fold; lower 95% credible limit [LCL], >1.6-fold) and Cmax (>1.8-fold; LCL, >1.2-fold) of intraperitoneal TIG. The TIG double dose produced somewhat larger increases. With oral TIG, oral ELA markedly increased plasma AUCtlast (>1.8-fold; LCL, >1.6-fold) in both strains, though Cmax increases were more modest (LCLs, ∼ 1). Coadministration with VORI transiently (0.25-0.5 hours) raised plasma TIG, with oral VORI producing greater effects than intraperitoneal VORI. Oral ELA markedly increases systemic exposure to TIG, suggesting that P-gp/BCRP efflux restricts gastrointestinal absorption and increases systemic elimination. Results with VORI suggest that intestinal metabolism further limits oral uptake. Thus, efflux pump inhibition may be a viable strategy to improve TIG therapy. SIGNIFICANCE STATEMENT: Blocking efflux pumps by elacridar in the gut, liver, and brain increases tigecycline absorption and systemic retention. Coadministration of voriconazole, an inhibitor of metabolism, also suggests a significant role of intestinal metabolism in restricting tigecycline's oral bioavailability.