Carrier-mediated uptake and excretion of bromosulfophthalein-glutathione in perfused rat liver: A multiple indicator dilution study

Geng, Wan; Schwab, Andreas; Goresky, Carl A.; Pang, K. Sandy

doi:10.1002/hep.1840220427

Cited by 28 publications

(46 citation statements)

References 40 publications

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“…Before surgery, animals were anesthetized with an intraperitoneal injection of 50 mg/kg sodium phenobarbital. The surgical procedure and perfusion apparatus were identical to those described previously (Geng et al, 1995). Perfusate consisted of 20% washed fresh bovine RBCs (a kind gift of Ryding Regency Meat Packers Ltd., Toronto, ON, Canada), 4% BSA, 5 mM glucose, and a complement of 20 amino acids in Krebs-Henseleit bicarbonate solution buffered to pH 7.4 and was oxygenated with carbogen (95% oxygen and 5% carbon dioxide; Matheson, Mississauga, ON, Canada).…”

Section: Liver Perfusion Systemmentioning

confidence: 99%

“…Only one concentration was used for each perfusion study. An O (0.096 Ϯ 0.013 ml) was introduced into the inflow system by an electronically controlled HPLC injection valve at 30 min, as described previously (Geng et al, 1995). Outflow samples were rapidly collected immediately at successive 1-(35 samples), 2-(35 samples), and 3-s (20 samples) intervals.…”

Section: Liver Perfusion Systemmentioning

confidence: 99%

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Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation

Doherty

Poon²,

Tsang³

et al. 2006

J Pharmacol Exp Ther

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Binding, transport, and metabolism are factors that influence morphine (M) removal in the rat liver. For M and the morphine 3␤-glucuronide metabolite (M3G), modest binding existed with 4% bovine serum albumin (unbound fractions of 0.89 Ϯ 0.07 and 0.98 Ϯ 0.09, respectively), and there was partitioning of M into red blood cells. Transport studies of M (Ͻ750 M) showed similar, concentration-independent uptake clearances (CLs) of 1.5 ml min Ϫ1 g Ϫ1 among zonal and homogeneous, isolated rat hepatocytes. Transport of M3G, ascertained in multiple indicator dilution studies at various steady-state M3G concentrations (10 -262 M), uncovered a low and concentration-independent influx clearance (Ͻ10% of flow rate). The outflow dilution curve of [ 3 H]M3G was superimposable onto that of [ 14 C]sucrose, the extracellular reference, displaying similarity in transit times (23.5 and 22.2 s), negligible biliary excretion, and almost complete dose recovery from perfusate. In contrast, M3G occurred abundantly in both perfusate and bile in single-pass perfusion studies of the precursor, M, and revealed a biliary clearance of formed M3G that was 12.3-fold that of preformed M3G, suggesting a sinusoidal, diffusional barrier for M3G. With increasing concentrations of M (9 -474 M), clearance decreased, and metabolism and biliary excretion displayed concentration-dependent kinetics. Fitting of the data to a physiologically based liver model revealed that M removal mechanisms were saturable, with a K m,met of 52.2 M and V max,met of 58.8 nmol min Ϫ1 g Ϫ1 for metabolism, and a K m,ex of 41.2 M and V max,ex of 8.1 nmol min Ϫ1 g Ϫ1 for excretion. Sinusoidal transport was not rate-limiting for M removal.

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Section: Liver Perfusion Systemmentioning

confidence: 99%

Section: Liver Perfusion Systemmentioning

confidence: 99%

Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation

Doherty

Poon²,

Tsang³

et al. 2006

J Pharmacol Exp Ther

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“…R6: Previous studies have determined a maximum uptake rate for BSP-GSH of 50 ^mole/hr (for a 10 g liver) (Geng et al, 1995). Since this is so close to the 60 (imole/hr value used for BSP uptake (R2), the decision was made to make both UAmax values equal to 60 nmole/hr.…”

Section: Sinusoidal Membrane Transportmentioning

confidence: 99%

“…Its value was iteratively determined. The presence of a second low affinity transport system for BSP transport has been documented before (Sorrentino et al, 1994;Schwenk et al, 1976).R6: Previous studies have determined a maximum uptake rate for BSP-GSH of 50 ^mole/hr (for a 10 g liver) (Geng et al, 1995). Since this is so close to the 60 (imole/hr value used for BSP uptake (R2), the decision was made to make both UAmax values equal to 60 nmole/hr.…”

mentioning

confidence: 99%

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Summer Research Program - 1998 Summer Research Extension Program Volume 1 Armstrong Laboratory

Moore¹

1998

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PubSc report™ bunlen for this collection of information is estimated to average 1 hour per response, including the time for reviewing, instructions, searcl the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information^incWng sugg« AUTHOR(S)Gary Moore PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Research & Development Laboratories (RDL) 5800 Uplander Way Culver City, CA 90230-6608 The United States Air Force Summer Research Program (SRP) is designed to introduce university, college, and technical institute faculty members to Air Force research. This is accomplished by the faculty members, graduate students, and high school students being selected on a nationally advertised competitive basis during the summer intersession period to perforn research at Air Force Research Laboratory (AFRL) Technical Directorates and Air Force Air Logistics Centers (ALC). AFOSR also offers its research associates (faculty only) an opportunity, under the Summer Research Extension Program (SREP), to continue their AFOSR-sponsored research at their home institutions through the award of research grants. This volume consists of the SREP program background, management information, statistics, a listing of the participants, and the technical report for each participant of the SREP working at the AF Armstrong Laboratory. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES)Air SUBJECT TERMS J GENERAL INSTRUCTIONS FOR COMPLETING SF 298The Report Documentation Page (RDP) is used in announcing and cataloging reports. It is important that this information be consistent with the rest of the report, particularly the cover and title page. Instructions for filling in each block of the form follow. It is important to stay within the fines to meet optical scanning requirements. Block 1. Agency Use Only (Leave blank).Block 2. Report Date. Full publication date including day, month, and year, if available (e.g. 1 Jan 88). Must cite at least the year.Block 3. Type of Report and Dates Covered. State whether report is interim, final, etc. If applicable, enter inclusive report dates (e.g. 10Jun87-30Jun88).Block 4. Title and Subtitle. A title is taken from the part of the report that provides the most meaningful and complete information. When a report is prepared in more than one volume, repeat the primary title, add volume number, and include subtitle for the specific volume. On classified documents enter the title classification in parentheses.Block 5. Funding Numbers. To include contract and grant numbers; may include program element number(s), project number(s), task number(s), and work unit number(s). Use the following labels:C -Contract G -Grant PE-Program ElementPR -Project TA ■ Task WU -Work Unit Accession No.Block 6. Author(s). Name(s) of person(s) responsible for writing the report, performing the research, or credited with the content of the report. If editor or compiler, this should follow the name(s). Block 7.Performing Organization Name(s) and Address(es). Self-explanatory.B...

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Carrier-mediated entry of 4-methylumbelliferyl sulfate: Characterization by the multiple-indicator dilution technique in perfused rat liver

Chiba¹,

Schwab²,

Goresky³

et al. 1998

Hepatology

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The hepatocellular entry of 4-methylumbelliferyl sulfate (4MUS) a highly ionized and highly bound anion capable of futile cycling, was examined in the single-pass albumin-free perfused rat liver preparation. Desulfation of 4MUS to 4-methylumbelliferone (4MU) was verified in vitro to be a low-affinity, high-capacity process (Km = 731 micromol/L; Vmax = 414 nmol min(-1) g(-1) liver). With 4MUS given to the perfused rat liver, sulfation of 4MU, the formed metabolite, was attenuated in the presence of 2,6-dichloro-4-nitrophenol (DCNP), a sulfation inhibitor, and when sulfate ion was substituted by chloride ion. 4MU sulfation, being a high-affinity system, was reduced most effectively at the lowest 4MUS concentration (15 micromol/L) used, evidenced by the increased (24%) net hepatic extraction ratio of 4MUS and reduced utilization (72%) of infused tracer 35SO4(2-) by 4MU for 4MU35S formation. Single-pass multiple indicator dilution (MID) studies were thus conducted under identical conditions (DCNP and absence of inorganic sulfate), with injection of [3H]4MUS and a set of noneliminated vascular and cellular reference indicators into the portal vein (prograde) or hepatic vein (retrograde), against varying background bulk concentrations of 4MUS (5 to 900 micromol/L). The steady-state removal rate of 4MUS and formation rates of 4MU and its glucuronide conjugate (4MUG) were not altered with perfusion flow direction, suggesting the presence of even or parallel distributions of 4MUS desulfation and 4MU glucuronidation activities. When the outflow dilution profile of [3H]4MUS was evaluated with the barrier-limited model of Goresky, a slight red cell carriage effect was found for 4MUS. The permeability surface area product for cellular entry for prograde showed a dramatic concentration-dependent decrease (from 0.13 to 0.01 mL sec(-1) g(-1), or 7.4 to 0.56 times the blood perfusate flow rate) and was resolved as saturable and nonsaturable components, while data for retrograde were more scattered, varying from 2.8 to 1 times the blood perfusate flow rate. Efflux (coefficient = 0.0096 +/- 0.0024 and 0.0088 +/- 0.0062 mL sec(-1) g(-1), respectively) was relatively insensitive to concentration and flow direction. The same was observed for the removal capacity for metabolism and excretion (sequestration coefficient: for prograde, 0.0056 +/- 0.0017 mL sec(-1) g(-1); for retrograde, 0.0056 +/- 0.003 mL sec(-1) g(-1)). The decrease in the apparent partition coefficient (ratio of 4MUS concentration estimated in tissue to unbound plasma concentration) and the increase in relative throughput component with concentration further substantiate the claim on the presence of concentrative processes at the sinusoidal membrane.

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Carrier-mediated uptake and excretion of bromosulfophthalein-glutathione in perfused rat liver: A multiple indicator dilution study

Cited by 28 publications

References 40 publications

Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation

Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation

Summer Research Program - 1998 Summer Research Extension Program Volume 1 Armstrong Laboratory

Carrier-mediated entry of 4-methylumbelliferyl sulfate: Characterization by the multiple-indicator dilution technique in perfused rat liver

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