The long-term goal of the research proposal is to provide a thorough understanding of the space- and time-related changes associated with drug disappearance and metabolite formation in the liver, the major drug biotransformation organ. Methods for probing zonal metabolic heterogeneities: normal-retrograde (NR) perfusion and hepatic artery- portal vein, hepatic artery-hepatic vein (HAPV-HAHV) once-through rat liver perfusions, and the technique of multiple indicator dilution will be used to examine mechanisms of elimination and transport across hepatocyte membranes for several precursor-metabolite pairs. Following an injection of a mixture of vascular (51Cr-labeled red blood cells, 125I-labeled albumin, 58Co-EDTA which behaves similarly as 14C-sucrose) and cellular (D2O) markers and 14C- and 3H-labeled precursor and product during steady- state bulk perfusion by NR (portal or hepatic vein) and HAPV-HAHV (substrate and injection into hepatic artery), a set of indicator dilution outflow profiles are obtained. The physiological volumes, and the influx, efflux, and sequestration coefficients for precursor and metabolite may be obtained after appropriate modeling approaches. Specifically, the hepatic processing of acetaminophen-acetaminophen sulfate, salicylamide- salicylamide sulfate, enalapril-enalaprilat, morphine-morphine glucuronide, 4-methylumbelliferone-4-methylumbelliferyl conjugates and harmol-harmol conjugates (with and without deconjugation inhibitors, sodium sulfite, D- saccharo-1-4-lactone or D-glucarolactone) will be studied, as these represent simple (one step, two steps, and parallel) biotransformation pathways. Moreover, the role of the hepatic artery in hepatic drug and metabolite processing will be investigated with intravital microscopy, 14C- phenacetin and 3H-acetaminophen extraction data, and the technique of multiple indicator dilution, when the portal vein/hepatic artery flow ratios are altered. The results should lend important insights into mechanisms of drug-metabolite processing, the differential fates of metabolites, when generated intracellularly or when administered into the organ, due to the differing points of origin, reversible-futile metabolism, and on the role of the hepatic artery in hepatic metabolism. This work will also explain precursor-product relationships involved in drug- metabolite mediated toxicity/activity and improve the designs of prodrugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038250-06
Application #
2179232
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1991-02-01
Project End
1995-01-31
Budget Start
1993-02-01
Budget End
1995-01-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Toronto
Department
Type
DUNS #
259999779
City
Toronto
State
ON
Country
Canada
Zip Code
M5 1-S8
Pang, K S; Schwab, A J; Goresky, C A et al. (1994) Transport, binding, and metabolism of sulfate conjugates in the liver. Chem Biol Interact 92:179-207
Xu, X; Schwab, A J; Barker 3rd, F et al. (1994) Salicylamide sulfate cell entry in perfused rat liver: a multiple-indicator dilution study. Hepatology 19:229-44
Pang, K S; Sherman, I A; Schwab, A J et al. (1994) Role of the hepatic artery in the metabolism of phenacetin and acetaminophen: intravital microscopic and multiple-indicator dilution study in perfused rat liver. Hepatology 20:672-83
Chiba, M; Poon, K; Hollands, J et al. (1994) Glycine conjugation activity of benzoic acid and its acinar localization in the perfused rat liver. J Pharmacol Exp Ther 268:409-16
Pang, K S; Barker 3rd, F; Schwab, A J et al. (1994) Demonstration of rapid entry and a cellular binding space for salicylamide in perfused rat liver: a multiple indicator dilution study. J Pharmacol Exp Ther 270:285-95
Ratna, S; Chiba, M; Bandyopadhyay, L et al. (1993) Futile cycling between 4-methylumbelliferone and its conjugates in perfused rat liver. Hepatology 17:838-53
Chiba, M; Pang, K S (1993) Effect of protein binding on 4-methylumbelliferyl sulfate desulfation kinetics in perfused rat liver. J Pharmacol Exp Ther 266:492-9
Goresky, C A; Pang, K S; Schwab, A J et al. (1992) Uptake of a protein-bound polar compound, acetaminophen sulfate, by perfused rat liver. Hepatology 16:173-90
St-Pierre, M V; Lee, P I; Pang, K S (1992) A comparative investigation of hepatic clearance models: predictions of metabolite formation and elimination. J Pharmacokinet Biopharm 20:105-45
Pang, K S; Xu, X; St-Pierre, M V (1992) Determinants of metabolite disposition. Annu Rev Pharmacol Toxicol 32:623-69

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