Renal excretion of emtricitabine II. Effect of trimethoprim on emtricitabine excretion: In vitro and in vivo studies

Abstract

The potential interaction between the nucleoside analog emtricitabine (FTC) and trimethoprim (TMP) was assessed in the isolated perfused rat kidney (IPK) model and in vivo in rats. IPK experiments were performed with FTC alone (2 µg/mL) and in the presence of increasing concentrations of TMP (1–10 µg/mL). TMP inhibited FTC excretion in a concentration dependent manner. The IC50 (TMP concentration associated with a 50% reduction in FTC excretion) was 1.86 ± 0.37 µg/mL. The results were compared to whole animal studies in rats. Animals received an IV dose of FTC (1 mg/kg) with or without pretreatment with TMP (25 mg/kg). TMP coadministration significantly decreased FTC clearance (7.4 ± 1.2 mL/min/kg to 2.7 ± 0.53 mL/min/kg), and elimination half‐life was significantly increased (58 ± 12 min to 215 ± 44 min). A good correlation was obtained between IPK findings and in vivo data, as FTC renal clearance was reduced ∼60% in the presence of TMP in both studies. Based on this investigation, TMP would be expected to inhibit the renal excretion of FTC when the two compounds are coadministered, resulting in increased plasma exposure of FTC. However, the clinical significance of this finding remains to be elucidated. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5411–5420, 2008