First-pass metabolism of peptide drugs in rat perfused liver

To elucidate the extent and mechanisms of the first-pass metabolism of pept ide drugs in the liver after oral administration, a liver perfusion study w as performed in rats using metkephamid, a stable analogue of methionine enk ephalin, and thyrotropin-releasing hormone (TRH), as model peptides. The fraction of intact metkephamid recovered after single-pass constant per fusion through rat liver reached steady-state very quickly, and it was conc luded that metkephamid was hydrolysed enzymatically at. the surface of hepa tocytes or endothelial cells of microvessels, or both, rather than being ta ken up by hepatocytes, The fraction of metkephamid recovered intact was app roximately 40% under protein-free conditions but increased to 70-75% on add ition of bovine serum albumin (BSA) to the perfusate, The fraction of metke phamid bound to BSA was approximately 50% under these conditions, implying that only the free fraction of metkephamid in the plasma was metabolized in the liver. Calculations based on the tube model showed that approximately 30-35% of metkephamid absorbed from the intestine undergoes first-pass meta bolism before entering the systemic circulation in-vivo. In contrast, the f raction of TRH metabolized in the liver was less than 10%, indicating a rem arkably low contribution of first-pass metabolism to the bioavailability of TRH. These results show that hepatic first-pass metabolism of metkephamid contri butes to its low systemic bioavailability. After intestinal absorption free metkephamid is rapidly hydrolysed on the surface of hepatocytes or endothe lial cells, rather than being taken up by hepatocytes. This information has important implications in the oral delivery of many kinds of peptide.