The effect of SKF-525A and of altered hepatic blood flow on lidocaine clearance in the cat

1977 ◽  
Vol 55 (1) ◽  
pp. 7-12 ◽  
Author(s):  
W. Wayne Lautt ◽  
F. Steve Skelton
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Intravenous Infusion ◽  
Intramuscular Injection ◽  
Hepatic Clearance ◽  
Hepatic Uptake ◽  
Extraction Ratio ◽  
Hepatic Extraction ◽  
Vascular Conductance ◽  
Altered Blood

Hepatic blood flow and hepatic uptake of lidocaine were determined in cats during constant intravenous infusion of lidocaine. Lidocaine clearance is directly linked to hepatic blood flow with reductions in flow being reflected in equal reductions in hepatic clearance. Altered blood flow did not result in altered rates of lidocaine extraction. Lidocaine extraction ratio was 28%.Hepatic blood flow and lidocaine metabolism were measured before and 60 min after an intramuscular injection of SKF-525A (50 mg/kg). SKF-525A produced a reduction in hepatic clearance of lidocaine to 60% of control values, entirely as a result of a reduction in hepatic extraction ratios. Hepatic blood flow and vascular conductance were not affected by SKF-525A.

Review of Cimetidine Drug Interactions

1983 ◽  
Vol 17 (2) ◽  
pp. 110-120 ◽  
Author(s):  
Eugene M. Sorkin ◽  
Diane L. Darvey
Keyword(s):  
Blood Flow ◽  
Drug Interactions ◽  
Hepatic Blood Flow ◽  
Hepatic Clearance ◽  
Hepatic Metabolism ◽  
Rapid Onset ◽  
Related Drug ◽  
Cytochrome P 450 ◽  
Acid Labile ◽  
Hepatic Cytochrome

The literature on cimetidine drug interactions has been thoroughly reviewed. Several different mechanisms have been proposed for cimetidine-related drug interactions. These mechanisms include: (1) impaired hepatic drug metabolism due to inhibition of hepatic microsomal enzymes, (2) reduced hepatic blood flow, resulting in decreased clearance of drugs that are highly extracted by the liver, (3) increased potential for myelosuppression when administered concurrently with other drugs capable of causing myelosuppression, and (4) altered bioavailability of acid-labile drugs. Cimetidine binds reversibly to the hepatic cytochrome P-450 and P-448 systems, resulting in decreased metabolism of drugs that undergo Phase I reactions (e.g., dealkylation and hydroxylation). In contrast, glucuronidation pathways are unaffected. The rapid onset and reversal of cimetidine's inhibition of hepatic metabolism indicates an effect on hepatic enzyme systems. Cimetidine also has been reported to decrease hepatic blood flow. Drugs that are highly extracted by the liver, such as propranolol, lidocaine, and morphine, may be postulated to have a decreased hepatic clearance. Cimetidine, through its effect on gastric pH, may increase the absorption of acid-labile drugs or may decrease the absorption of drugs. There have been reports of increased potential for myelosuppression when cimetidine is administered concurrently with drugs capable of causing bone marrow suppression. An understanding of the mechanisms involved in cimetidine drug interactions allows the clinician to prevent and predict these interactions.

Nicardipine increases hepatic blood flow and the hepatic clearance of ICG in patients with cirrhosis

1990 ◽  
Vol 11 ◽  
pp. S24
Author(s):  
JC García-Paqán ◽  
F Feu ◽  
L Ruiz del Arbol ◽  
I Cirera ◽  
P Pizcueta ◽  
...  
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Hepatic Clearance

Nicardipine increases hepatic blood flow and the hepatic clearance of indocyanine green in patients with cirrhosis

1994 ◽  
Vol 20 (6) ◽  
pp. 792-796 ◽  
Author(s):  
Juan Carlos García-Pagán ◽  
Fausto Feu ◽  
Angelo Luca ◽  
Mercedes Fernández ◽  
Pilar Pizcueta ◽  
...  
Keyword(s):  
Blood Flow ◽  
Indocyanine Green ◽  
Hepatic Blood Flow ◽  
Hepatic Clearance

EXTRAHEPATIC METABOLISM OF RECOMBINANT TISSUE-TYPE PLASMINOGEN ACTIVATOR (tPA) IN DOGS

1987 ◽  
Author(s):  
K L L Fong ◽  
K E Boyle ◽  
C S Crysler ◽  
M S Landi ◽  
H E Griffin ◽  
...  
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Systemic Circulation ◽  
Volume Of Distribution ◽  
Hepatic Uptake ◽  
Tissue Type ◽  
Systemic Clearance ◽  
Artery Ligation ◽  
Β Phase

Hepatic uptake has been proposed as the major mechanism of tPA clearance from systemic circulation. However, our recent studies demonstrated that tPA was rapidly Inactivated through complexation with protease Inhibitors in dog plasma In vitro, and that tPA-inhibitor complexes were present in plasma of dogs receiving tPA. Therefore, the present work was undertaken to differentiate hepatic from extrahepatlc clearance of tPA. Pharmacokinetics of tPA were determined in anesthetized beagle dogs with either Intact hepatic circulation or with Interrupted hepatic blood flow achieved by hepatic artery ligation and portal caval shunt.Recombinant two-chain tPA was administered as an Intravenous bolus dose (80 μg/kg) and plasma active tPA concentrations were measured using a modified and validated S-2251 chromogenlc assay. Following tPA administration to Intact dogs, plasma active tPA concentration declined blexponentlally with time with 84% of the active tPA eliminated during the α-phase. The t1/2's of the a and β-phase were 1.76 ± 0.74 and 6.23 ± 1.56 min, respectively. The systemic clearance was 25.98 ± 1.13 ml/min/kg and the volume of distribution at steady state (VDss) was 73.9 ± 15.1 ml/kg. Upon the elimination of hepatic blood flow, the systemic clearance was reduced by 54% while VDss was unaffected. The contribution of plasma Inactivation of tPA to the systemic clearance was estimated from in vitro Inactivation studies In 37°C plasma. Based on the pseudo first order Inactivation rate constants of 0.184 min-1 and 0.095 min-1 at Initial tPA concentrations of 25 and 250 IU/ml respectively, clearance rates from 5.02 to 9.2 ml/min/kg were calculated. These data suggest that (1) in Intact dogs, 46% of the tPA clearance occurs extrahepatlcally and (2) Inactivation of tPA in plasma accounts for a major portion of the extrahepatlc clearance.

Derecruitment in cat liver: extension of undistributed parallel tube model to effects of low hepatic blood flow on ethanol uptake

1989 ◽  
Vol 67 (10) ◽  
pp. 1225-1231 ◽  
Author(s):  
C. V. Greenway ◽  
L. Bass
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Venous Pressure ◽  
Liver Blood Flow ◽  
Hepatic Uptake ◽  
Tube Model ◽  
Low Flows ◽  
Wide Range ◽  
Parallel Tube ◽  
Parallel Tube Model

Previous studies showed two deviations from the predictions of the undistributed parallel tube model for hepatic uptake of substrates: a small deviation at high flows and a large deviation at low flows. We have examined whether these deviations could be described by a single correction factor. In cats anesthetized with pentobarbital, a hepatic venous long-circuit technique with an extracorporeal reservoir was used to vary portal flow and hepatic venous pressure, and allow repeated sampling of arterial, portal, and hepatic venous blood without depletion of the cat's blood volume. Hepatic uptake of ethanol was measured over a wide range of blood flows and when intrahepatic pressure was increased at low flows. This uptake could be described by the parallel tube model with a correction for hepatic blood flow: [Formula: see text]. In 22 cats, [Formula: see text], k = 0.021 ± 0.0015 when flow (F) was in millilitres per minute per 100 g liver, and Km = 150 ± 20 μM when ĉ is the log mean sinusoidal concentration. (1 − e−kF) represents the proportion of sinusoids perfused and metabolically active. A dynamic interpretation of this proportion is related to intermittency (derecruitment) of sinusoidal flow. Half the sinusoids were perfused at a flow of 33 mL/(min∙100 g liver) and the liver was essentially completely perfused (> 95%) at the normal flow of 150 mL/(min∙100 g liver). Derecruitment was not changed by raising hepatic venous pressure, and it was not related to hepatic venous resistance.Key words: liver circulation, ethanol metabolism, liver blood flow, sinusoidal perfusion, portal pressure.

Regulation of Gluconeogenesis and Ketogenesis during Rest and Exercise in Diabetic Subjects and Normal Men

1977 ◽  
Vol 53 (5) ◽  
pp. 411-418 ◽  
Author(s):  
L. Sestoft ◽  
J. Trap-Jensen ◽  
J. Lyngsøe ◽  
J. P. Clausen ◽  
J. J. Holst ◽  
...  
Keyword(s):  
Blood Flow ◽  
Hepatic Blood Flow ◽  
Ketone Bodies ◽  
Venous Blood ◽  
Hepatic Metabolism ◽  
Hepatic Uptake ◽  
Diabetic Group ◽  
Hepatic Venous Blood ◽  
Juvenile Diabetic ◽  
Normal Men

1. The splanchnic—hepatic metabolism of glucose, lactate, pyruvate, alanine, glycerol, non-esterified fatty acids (NEFA), ketone bodies and oxygen were investigated in five normal men and six juvenile diabetic subjects at rest and during exercise after an overnight fast. 2. A linear relationship was found between load (arterial concentration multiplied by hepatic blood flow) and splanchnic—hepatic uptake of lactate, pyruvate, glycerol and NEFA. The uptake of alanine was highly sensitive to load, but was also regulated by the concentration of hepatic venous glucagon. The uptake of pyruvate was high in exercising diabetic subjects, who had a high lactate/pyruvate concentration ratio in hepatic venous blood. 3. The rate of uptake of the total measured gluconeogenic precursors was significantly higher in the diabetic group at a given load. 4. The rate of ketogenesis was linearly related to the NEFA load in both groups; however, the rate of ketogenesis was twofold at a given load in the diabetic group. The highest rates of ketogenesis were found coincident with the highest concentrations of glucagon in hepatic venous blood. 5. The observed antiketogenic effect of exercise was due to a decreased load of NEFA, mainly caused by a decrease in the hepatic blood flow.

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