Application of physiologically based (PBK) modeling to quantify the effect of the antibiotic tobramycin on bile acid levels in human plasma

Abstract

Systemic bile acid homeostasis plays an important role in human health. In this study, a physiologically based kinetic (PBK) model that includes microbial bile acid deconjugation and intestinal bile acid reuptake via the apical sodium-dependent bile acid transporter (ASBT) was applied to predict the systemic plasma bile acid concentrations in human upon oral treatment with the antibiotic tobramycin. Tobramycin was previously shown to inhibit intestinal deconjugation and reuptake of bile acids and to affect bile acid homeostasis upon oral exposure of rats. Kinetic parameters to define the effects of tobramycin on intestinal bile acid transport were determined in vitro using a Caco-2 cell layer Transwell model for studying the intestinal translocation of 4 model bile acids including glycochenodeoxycholic acid (GCDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and deoxycholic acid (DCA), the latter as a model for unconjugated bile acids (uBA). Kinetic constants for the effect of tobramycin on intestinal microbial deconjugation were taken from previous in vitro studies using anaerobic fecal incubations. The PBK model simulations predicted that exposure to tobramycin at the dose level also used in the previous 28 day rat study would reduce human plasma C_max levels of GCA, GCDCA, GDCA, and DCA by 42.4%, 27.7%, 16.9%, and 75.8%. The reduction of conjugated bile acids is governed especially via an effect on ASBT-mediated intestinal uptake, and not via the effect of tobramycin on intestinal conjugation, likely because deconjugation happens to a large extent in the colon which has limited subsequent bile acid reuptake. The results reflect that oral exposure to xenobiotics that are not or poorly bioavailable can affect systemic bile acid homeostasis. Altogether, the PBK model appears to provide a 3R compliant tool to evaluate the effect of oral exposure to xenobiotics on host bile acid homeostasis via effects on intestinal bile acid deconjugation and reuptake.

Keywords: Apical sodium-dependent bile acid transporter (ASBT); Bile acids; Caco-2 cells; Physiologically based kinetic (PBK) model; Tobramycin.