REVERSAL OF STEREOSELECTIVITY IN THE HEPATIC AVAILABILITY OF VERAPAMIL IN ISOLATED-PERFUSED RAT LIVERS - ROLE OF PROTEIN-BINDING

The effects of serum proteins on the stereoselective kinetics of the h igh clearance drug verapamil (VER) and its metabolite, norverapamil (N OR), were studied in isolated perfused rat livers (IPRLs), Livers were perfused, in a recirculating manner, with a solution containing human serum albumin (HSA), bovine serum albumin (BSA), or no serum albumin (N = 5 for each group). After presystemic administration of a single d ose of racemic VER (2 mg), the concentrations of VER and NOR enantiome rs in the perfusate were measured over 90 min. In addition, the fracti on of the enantiomers bound to tile plasma of perfusate was determined . Perfusate concentrations of both VER and NOR were stereoselective in all of the perfusates studied. However, the direction of stereoselect ivity in the concentrations of VER enantiomers in the BSA perfusate (S -VER > R-VER) was opposite that in the HSA and albumin-free perfusates (R-VER > S-VER); this was associated with an opposite stereoselectivi ty in the free fractions of VER in the HSA (S-VER > R-VER) and BSA (R- VER > S-VER) perfusates. Furthermore, the extent of stereoselectivity in the concentrations of NOR in the BSA perfusate was higher than that in the HSA and albumin-free perfusates, an observation in agreement w ith the higher stereoselectivity in the binding of NOR to BSA, These d ata, along with other kinetic parameters such as apparent hepatic avai lability and intrinsic clearance, suggest that the apparent stereosele ctivity in the presystemic elimination of VER by IPRLs is significantl y influenced by the stereoselectivity in the protein binding of the dr ug.