- Purpose: To investigate a novel mechanism for oral controlled release of drugs involving a continuous degradation of a phospholipid prodrug along the intestine. An indomethacin–lecithin conjugate with the drug attached to the sn-2 position of the phospholipid through a 5-carbon linker (DP-155) was used as a model molecule. Methods: The pharmacokinetics of DP-155 and free indomethacin liberated from the prodrug following intravenous, oral or intra-colon administration was investigated in rats, and evaluated in comparison to free indomethacin administration. Degradation by phospholipase A2 (PLA2) enzymes was assessed in-vitro. The impact of the linker length was evaluated in comparison to an indomethacin–phospholipid conjugate with a shorter linker (2-carbons). Results: Following oral or intra-colon DP-155 administration, free indomethacin was liberated along the intestine and absorbed into the systemic circulation, resulting in a controlled release profile of indomethacin in the plasma. The shorter linker caused a 20-fold decrease in the subsequent indomethacin absorption. DP-155 in-vitro degradation by PLA2 was over 60%, while shorter linkers were profoundly less degradable. Conclusions: DP-155 caused a continuous input of free indomethacin into the plasma following degradation by PLA2 in the gut lumen. Since the rate of drug release is not formulation dependent, the prodrug can be compounded even in a liquid dosage form. The phospholipid–drug conjugate is thus a potential novel mechanism for oral controlled release of drugs. © 2007 Elsevier B.V. All rights reserved.