COMPARATIVE HEPATIC TRANSPORT OF DESGLYCYLATED AND CYCLIC METABOLITESOF RILMAZAFONE IN RATS - ANALYSIS BY MULTIPLE INDICATOR DILUTION METHOD

Rilmazafone (RZ) is an orally active sleep inducer which can be activa ted to its cyclic form (M 1) via the labile desglycylated metabolite ( DG). In this scheme, RZ is exclusively metabolized to DG and Ml by ami nopeptidases in the small intestine. The concentration of M1 in the sy stemic plasma after oral administration of RZ has been reported to be higher than that observed after administration of M1, due to the lower hepatic extraction of DG than M1 (Koike et al., Drug Metab. Dispos., 16, 609 (1988)). In the present study, the disposition of DG and M1 in rat liver was investigated, using the multiple indicator dilution met hod. The hepatic availabilities (F) of DG and M1, assessed from the re covery into the hepatic vein, were 0- 16 and 0.07, respectively, which was consistent with the previous in vivo finding that the first-pass elimination of M1 was greater than that of DG. The kinetic analysis ba sed on the distributed model showed that the influx (k1') and efflux ( k2') rate constants for M1 were larger than those for DG, whereas no s ignificant difference in the sequestration rate constant (k3') was obs erved between the two ligands. Based on the concept proposed by Miyauc hi et al. (J. Pharmacokinet. Biopharm., 15, 25 (1987)), it was suggest ed that the determinant factor of the hepatic intrinsic clearance was the influx clearance for both ligands, because the values of k2' for e ach ligand were much smaller than the respective k3' values. It was co ncluded that the higher plasma concentration of M1 after oral administ ration of RZ than that observed after administration of M1 is due to t he fact that the hepatic uptake of DG is lower than that of M 1.