Experimental studies of transient mass transfer and reaction in the liver: interpretation with a heterogeneous compartment model.
The uptake and metabolism of lipophilic compounds by the liver were studied by administering a model compound, lidocaine, to the isolated rat liver. Lidocaine was continuously infused into the liver until steady state was reached. Subsequent step changes in the inlet concentration were used to obtain information on rates of cellular uptake and release and to assess the extent of mixing within the organ. A simple heterogeneous model combining mass transfer and enzyme reactions was required to simulate the effluent levels of lidocaine and two primary metabolites, monoethylglycinexylidide and 3-hydroxylidocaine. The rate constants for uptake and release of lidocaine were 1200 and 46 min-1, respectively. The rate-limiting step was intracellular reaction, with a rate constant of 0.49 min-1. Although the rate of lidocaine uptake was fast, it was 50 times slower than the rate of facilitated uptake of galactose, a fact suggesting passive transport of lidocaine between the tissue and the vasculature. The rates of mass transfer of lidocaine and its metabolites differed, but the ratios of the rate of uptake to the rate of release were the same. The results suggested that all three species had an affinity for the cellular region of the liver; concentrations in tissue were approximately five times greater than concentrations in effluent. Because of the large capacity of the organ for uptake of lidocaine and its metabolites, concentrations from washout experiments were controlled by linear mass transfer from the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Saville
B A
BA
Department of Chemical Engineering, University of Alberta, Edmonton, Canada.
Gray
M R
MR
Tam
Y K
YK
D000818:Animals; D005110:Extracellular Space / Q000378:metabolism; D066298:In Vitro Techniques; D008012:Lidocaine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008432:Mathematical Computing; D008954:Models, Biological; D010599:Pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains
C075860:3-hydroxylidocaine; D008012:Lidocaine; C001173:monoethylglycinexylidide