Hepatic local disposition of a drug with high protein binding and high hepatic clearance using BOF-4272 as a model drug.
The local disposition of a drug, which is efficiently eliminated by the liver in spite of very high binding with serum albumin, was investigated using BOF-4272 as a model drug in the hepatic perfusion system. Bovine serum albumin (BSA) labeled with Evans Blue was used as the marker of hepatic blood space. The perfusion experiments were carried out at 37 degrees C and at 4 degrees C to evaluate the local disposition in active and inactive livers, respectively. The perfusates included 0, 0.25, 0.5, 1.0 and 4.0% of BSA in the injection of BOF-4272, and 0 and 1.0% of BSA in the injection of Evans Blue. After an instantaneous injection of BOF-4272 or Evans Blue (labeling reagent of BSA), the outflow time profile from the liver was analyzed by curve-fitting based on two-compartment dispersion model. All estimated parameters of BSA were almost the same between 37 degrees C and 4 degrees C, which showed that the blood space in the liver was unaffected by perfusate temperature. The recovery ratio (FH) and the mean transit time (FH) of BSA were 100% and about 0.1 min, respectively, both with BSA (1.0%) and without BSA in the perfusate. FH of BOF-4272 increased from 20% to 50% with an increase in the perfusate BSA at 37 degrees C, whereas FH was almost constant (90%) regardless of BSA concentration at 4 degrees C. FH of BOF-4272 was almost 0.1 min regardless of BSA concentration at 37 degrees C, whereas FH decreased from 0.29 min to 0.17 min at 4 degrees C with an increase in the perfusate BSA. A large elimination (10%) of BOF-4272 was noticed even at 4 degrees C in the presence of perfusate BSA, which demonstrates that the passive transfer of BOF-4272 from BSA to the hepatic tissues is considerably rapid. This efficient transfer is responsible for the large hepatic clearance of BOF-4272 with very high binding with BSA.
Laboratory of Drug Metabolism Research, Naruto Research Institute, Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan.
M
M
Nishimura
K
K
Yamaoka
S
S
Naito
T
T
Nakagawa
D000818:Animals; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008102:Liver Circulation / Q000502:physiology; D008297:Male; D008954:Models, Biological; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000493:pharmacokinetics; D013056:Spectrophotometry, Ultraviolet; D014227:Triazines / Q000493:pharmacokinetics*; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D014227:Triazines; D012710:Serum Albumin, Bovine; C072977:BOF 4272; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase