Comparative hepatic transport of desglycylated and cyclic metabolites of rilmazafone in rats: Analysis by multiple indicator dilution method

Abstract

Rilmazafone (RZ) is an orally active sleep inducer which can be activated to its cyclic form (M1) via the labile desglycylated metabolite (DG). In this scheme, RZ is exclusively metabolized to DG and M1 by aminopeptidases in the small intestine. The concentration of M1 in the systemic 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 method. The hepatic availabilities (F) of DG and M1, assessed from the recovery 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 based on the distributed model showed that the influx (k'1) and efflux (k'2) rate constants for M1 were larger than those for DG, whereas no significant difference in the sequestration rate constant (k'3) was observed between the two ligands. Based on the concept proposed by Miyauchi et al. (J. Pharmacokinet. Biopharm., 15, 25 (1987)), it was suggested that the determinant factor of the hepatic intrinsic clearance was the influx clearance for both ligands, because the values of k'2 for each ligand were much smaller than the respective k'3 values. It was concluded that the higher plasma concentration of M1 after oral administration of RZ than that observed after administration of M1 is due to the fact that the hepatic uptake of DG is lower than that of M1.

Analysis Methods and Recent Advances in Nonlinear Pharmacokinetics from In Vitro through In Loci to In Vivo

“…(11). 43) HED＝AD･( BWA W BWH) X-SF (11) where AD is animal dose, BWA and BWH are body weights of animal and human, respectively, and SF is scaling factor (unitless Direct method: This method is called``in loci'' in a narrow deˆnition. The blood concentration of a drug is usually the same in the systemic circulation (artery and vein), except for three sites.…”

“…Independently of linear or nonlinear systems, the well-stirred 6,7) and parallel-tube models 8,9) have been adopted to estimate drug elimination in perfusion experiments under steadystate conditions, whereas the distributed, 10,11) tank-inseries 12,13) and dispersion 14,15) models have been adopted to well explain the time proˆles under the nonsteady state conditions.…”