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 high clearance drug verapamil (VER) and its metabolite, norverapamil (NOR), 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 dose of racemic VER (2 mg), the concentrations of VER and NOR enantiomers in the perfusate were measured over 90 min. In addition, the fraction of the enantiomers bound to the plasma of perfusate was determined. Perfusate concentrations of both VER and NOR were stereoselective in all of the perfusates studied. However, the direction of stereoselectivity 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 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 with the higher stereoselectivity in the binding of NOR to BSA. These data, along with other kinetic parameters such as apparent hepatic availability and intrinsic clearance, suggest that the apparent stereoselectivity in the presystemic elimination of VER by IPRLs is significantly influenced by the stereoselectivity in the protein binding of the drug.
College of Pharmacy and Health Sciences, Drake University, Des Moines, IA 50311, USA.
R
R
Mehvar
J
J
Reynolds
D000818:Animals; D001682:Biological Availability; D008099:Liver / Q000378:metabolism*; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism*; D013237:Stereoisomerism; D014700:Verapamil / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*
D012709:Serum Albumin; D014700:Verapamil