Abstract
Metabolic zonation was assessed with the multiple indicator dilution (MID) technique in the single-pass perfused rat liver with use of moment analysis of the formed metabolite (M) data. During single-pass, retrograde rat liver perfusion with 17 μM benzoate, a bolus containing tracer preformed metabolite (PM) [3H]hippurate was injected rapidly into the hepatic vein at 20 min postperfusion, followed by injection of a second bolus containing [14C]benzoate at 30 min. Both doses also contained noneliminated reference indicators (51Cr-labeled RBCs,125I-labeled albumin, [14C]- or [3H]sucrose, and 2H2O). The steady-state extraction ratio of benzoate, the area under the curve (AUC) and its mean transit time (MTT) during retrograde flow were identical to those previously observed for prograde flow. Values of AUCPM and MTTPM and AUCM were also similar to previously published prograde data, but the MTTMwith retrograde perfusion was smaller than that for prograde perfusion. This, according to theory based on the tubes-in-series model, was consistent with perivenous enrichment of glycination activity when transport of drug was even and when the ratio of drug influx/efflux coefficient exceeded that for metabolite. Similar benzoate transport in periportal, homogeneous and perivenous isolated rat hepatocytes existed, and the influx/efflux coefficients (partition ratio) of benzoate from MID indeed exceeded that of hippurate. However, metabolism by zonal hepatocytes failed to reveal the anticipated metabolic zonation, and this is likely due to the shallow gradient of metabolic activity. The study demonstrates that moment theory is useful in delineating the perivenous enrichment of glycine conjugation activity.
Footnotes
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DOI: 10.1124/jpet.102.044024
- Abbreviations:
- HA
- hippuric acid
- HV
- hepatic vein
- PP
- periportal
- PV
- perivenous
- AUC
- area under the curve of benzoate
- AUCM
- area under the curve of formed metabolite
- AUCPM
- area under the curve of the preformed metabolite
- MTT
- mean transit time of benzoate
- MTTM
- mean transit time of the formed metabolite
- MTTPM
- mean transit time of the preformed metabolite
- HPLC
- high-performance liquid chromatography
- BA
- benzoic acid
- MID
- multiple indicator dilution
- GST
- glutathioneS-transferase
- Received September 6, 2002.
- Accepted January 3, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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