Consideration on moments of outflow profile in liver perfusion system with change in perfusate flow rate using oxacillin as model drug.
The effect of perfusate flow rate on hepatic structure and hepatic uptake kinetics was investigated using oxacillin as a model drug and bovine serum albumin (BSA) as a reference substance in the liver perfusion system from the standpoint of a dispersion model and moment characteristics. The estimated recovery ratio (FH) of oxacillin was about 40% which was independent of the change in perfusate flow rate. The mean transit time (tH) of oxacillin decreased with an increase in flow rate, while the relative variance (sigma 2/t2H) of oxacillin was independent of the flow rate. The tH of BSA decreased with an increase in the flow rate to the same extent as that of oxacillin, while sigma 2/t2H of BSA was independent of flow rate. When the dispersion model is adopted as a model system to analyze hepatic perfusion data following the pulse input, the moment characteristics (FH, tH and sigma 2/t2H) are given in complicated equations. It is demonstrated by the present investigation that these moment equations can be extensively simplified for a drug with a medium extraction ratio (FH > 50%), i.e., FH is independent of the distribution, both FH and tH are independent of the dispersion process in the hepatic blood space, and both tH and sigma 2/t2H are independent of the elimination. Thus, it is shown that FH and tH are exactly the indices of elimination and distribution, respectively, and sigma 2/t2H is the index of dispersion in the blood space plus nonequilibrium in the hepatic distribution.
Ohata
Y
Y
Faculty of Pharmaceutical Science, Kyoto University, Japan.
Yamaoka
K
K
Yasui
H
H
Nakagawa
T
T
D000818:Animals; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009929:Organ Size; D010068:Oxacillin / Q000493:pharmacokinetics*; D010406:Penicillins / Q000493:pharmacokinetics*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet
D010406:Penicillins; D012710:Serum Albumin, Bovine; D010068:Oxacillin