Intestinal behavior of the ester prodrug tenofovir DF in humans

Tenofovir-disoproxil-fumarate (TDF) is a double ester prodrug which enables intestinal uptake of tenofovir (TFV) after oral administration in humans. In this study, prodrug stability was monitored in situ in the human intestine and in vitro using biorelevant media. In fasted state human intestinal fluids, the prodrug was completely degraded within 90 min, resulting in the formation of the mono-ester intermediate and TFV; in fed state intestinal fluids, the degradation rate of TDF was slightly reduced and no TFV was formed. Intestinal fluid samples aspirated after administration of TDF confirmed extensive intraluminal degradation of TDF in fasted state conditions; a relatively fast absorption of TDF partly compensated for the degradation. Although food intake reduced intestinal degradation, the systemic exposure was not proportionally increased. The lower degradation in fed state conditions may be attributed to competing esterase substrates present in food, lower chemical degradation in the slightly more acidic environment and micellar entrapment, delaying exposure to the "degrading" intestinal environment. The results of this study demonstrate premature intestinal degradation of TDF and suggest that TFV may benefit from a more stable prodrug approach; however, fast absorption may compensate for fast degradation, indicating that prodrug selection should not be limited to stability assays.