Increase In Liver Blood Flow Research Articles

Sorafenib-loaded PAMAM dendrimer attenuates liver fibrosis and its complications in bile-duct-ligated rats.

We assessed the effect of sorafenib-loaded polyamidoamine (PAMAM) dendrimer on liver fibrosis induced by bile duct ligation (BDL). Male Wistar rats were divided into 9 groups: intact, sham, DMSO + BDL, BDL, sorafenib (30 mg/kg), sorafenib (60 mg/kg), PAMAM + BDL, sorafenib (30 mg/kg) + PAMAM + BDL, sorafenib (60 mg/kg) + PAMAM + BDL. BDL was induced and then rats were treated daily with sorafenib and (or) PAMAM for 4 weeks. Improvement of liver was detected via assessment of ascites formation, collagen deposition, liver blood flow, vascular endothelial growth factor level, and blood cells count. Sorafenib-loaded PAMAM dendrimer in both 30 and 60 mg/kg doses reduced ascites formation, reduced collagen deposition, and improved drug-induced hematological side effects of sorafenib alone in comparison with sorafenib-alone treatment. Sorafenib-loaded PAMAM dendrimer increased liver blood flow compared with sorafenib-received groups. Sorafenib-loaded PAMAM dendrimer reduced BDL-induced liver injury compared with sorafenib-received groups. Moreover, sorafenib-loaded PAMAM dendrimer decreased vascular endothelial growth factor level in serum and liver tissue in comparison with sorafenib-received groups. Sorafenib-loaded PAMAM dendrimer profoundly improved the therapeutic effects of sorafenib in BDL rats.

Effect of Flying at High Altitude on Early Exposure of Paracetamol in Humans.

Pharmacokinetics of paracetamol (APAP) was studied on-board during an air flight and compared to those on ground after 500 mg oral dose in 20 healthy human volunteer in parallel design study. Saliva samples were obtained every 15 min up to 2 h after dosing. Pharmacokinetic parameters were calculated by non compartmental analysis and one compartment models using Winnonlin program V5.2. Results have showed that on-board to ground ratios for area under curves AUC0→1, AUC0→2, time to reach maximum saliva concentration Tmax, absorption rate constant Ka and maximum saliva concentration Cmax were 0.62, 0.38, 1.01, 0.81 and 0.79 respectively. Effective membrane permeability coefficients were optimized by Nelder-Mead algorithm using Simcyp program V13. This showed similar rate of absorption and early exposure up to one hour, and lower bioavailability after 1 h on-board. This can be explained by the increased liver blood flow at high altitude that led to increased liver metabolism on-board. However, APAP elimination parameters were not calculated due to short sampling time. This suggests a need for dose adjustment on-board during long air flights, especially for narrow therapeutic index drugs with flow limited metabolism.

Investigation of mechanisms involved in regulation of progesterone catabolism using an overfed versus underfed ewe-lamb model.

Alterations in progesterone (P4) catabolism due to high feed intake underlie some effects of nutrition on reproduction. Based on previous research, we hypothesized that high feed intake could potentially increase P4 catabolism, likely due to increased liver blood flow. However, there could also be an opposing action due to increased circulating insulin, which has been shown to inhibit hepatic expression of key enzymes involved in P4 catabolism. To test which effect would have the greatest impact on circulating P4 during a 1- and 2 -mo time frame, we used a noncyclic ewe model. The plane of nutrition was controlled, and effects on circulating insulin, P4 catabolism in response to exogenous P4, and steady state mRNA for key hepatic enzymes were evaluated. Twenty-four F Dorper × Santa Inês ewe lambs (5 mo old and approximately 25 kg BW) were used. After 14 d of adaptation, ewes were randomized into 2 groups: ad libitum fed (Ad), with intake of 3.8% DM/kg BW, or restricted feed intake (R), with 2% DM/kg BW, for 8 wk. At wk 4 and 8, ewes received an intravaginal P4 implant to evaluate P4 catabolism. As designed, Ad ewes had greater daily feed intake than R ewes (means of 1.8 [SE 0.03] and 0.6 kg/ewe [SE 0.01]; < 0.001) and greater weekly gain in BW (means of 1.7 [SE 0.12] vs. -0.1 kg/ewe [SE 0.03]; < 0.001). Mean circulating insulin of samples collected from -0.5 to 7 h after the start of feeding was over 5-fold greater in Ad ewes than in R ewes (least squares means of 8.2 [SE 0.93] vs. 1.5 μIU/mL [SE 0.16], respectively, at wk 4 and 12.0 [SE 1.02] vs. 2.2 μIU/mL [SE 0.18], respectively, at wk 8; < 0.001). Although both groups received the same P4 treatment, mean circulating P4 of samples collected from -0.5 to 7 h after feeding was much lower in Ad ewes than in R ewes (least squares means of 3.2 [SE 0.32] vs. 5.5 ng/mL [SE 0.32], respectively, at wk 4 and 2.8 [SE 0.28] vs. 5.2 ng/mL [SE 0.28], respectively, at wk 8; < 0.001) indicating much greater P4 catabolism in ewes with high feed intake. Unexpectedly, there was no effect of diet on hepatic mRNA concentrations for , , , or at wk 4 or 8 in spite of dramatically elevated insulin. Therefore, high energy/feed intake primarily increased P4 catabolism with no evidence for offsetting effects due to insulin-induced changes in hepatic P4 metabolizing enzymes.

Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults.

BackgroundThe clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults.MethodsData from 19 obese adolescents [102.7 kg (62–149.5 kg)] and 20 morbidly obese adults [144 kg (112–186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WTfor age and length) and excess body weight (WTexcess = TBW − WTfor age and length) was evaluated.ResultsThe population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WTexcess, and for which a so-called ‘excess weight’ model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess was proposed.DiscussionWe hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WTexcess is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0579-4) contains supplementary material, which is available to authorized users.

The effect of food on the high clearance drug asenapine after sublingual administration to healthy male volunteers

To determine the effects of food on the pharmacokinetics of sublingual asenapine. Healthy male volunteers (n=26, age 19-53 years) randomly received a single sublingual dose of asenapine 5 mg after ≥ 10 h fasting (Treatment A, reference), after a high-fat meal (Treatment B) and after ≥ 10 h fasting with a high-fat meal at 4 h post-dose (Treatment C). Blood samples were drawn over 72 h to measure asenapine plasma concentrations. Effects of food intake on asenapine pharmacokinetics were assessed using bioequivalence criteria and evaluated using a compartmental modelling analysis. Compared with the reference, mean asenapine exposure (AUC0-last and AUC0-∞) was approximately 20 % lower after intake of a high-fat meal prior to dosing, whereas Cmax decreased by only about 10 %. When a high-fat meal was taken 4 h post-dose in the fasting state, asenapine concentrations were similar to the reference during the first 4 h post-dose. After the meal intake, asenapine concentrations decreased quickly for several hours. Compartmental modelling indicated that a transient 2.5-fold increase in asenapine clearance after eating could explain the asenapine concentration-time profiles for both food regimens. To our knowledge, this is the first study investigating the effect of food upon the sublingual administration of a drug. A high-fat meal taken before or 4 h post-dose of sublingual asenapine indirectly caused a transient increase in liver blood flow that resulted in a temporal increase in asenapine clearance. As the effects on asenapine exposure were small and not clinically relevant, no additional restrictions are required for the timing of food intake in relation to asenapine dosing.

Thoracic but not lumbar epidural anaesthesia increases liver blood flow after major abdominal surgery

Epidural blockade in major abdominal surgery bears the potential to increase gastrointestinal perfusion and thus to improve patient outcome. The aim of this study was to assess the differential influence of thoracic and lumbar epidural anaesthesia and analgesia (EAA) on blood lactate levels and central venous oxygen saturation (ScvO2) as parameters of global oxygen supply/demand ratio, as well as on the plasma disappearance rate of indocyanine green (PDR(ICG)), a noninvasive method to evaluate liver perfusion. We enrolled 17 patients receiving thoracic and 17 patients receiving lumbar EAA in addition to general anaesthesia for major abdominal surgery. Lactate, ScvO2 and PDR(ICG) were measured postoperatively on the ICU. Subsequently, epidural application of local anaesthetics was started with a bolus of bupivacaine 0.25% (thoracic 10 ml, lumbar 12 ml) followed by continuous infusion of bupivacaine (thoracic 8 ml h(-1) 0.175%, lumbar 10 ml h(-1) 0.125%) and fentanyl (2 microg ml(-1)). Central venous pressure was maintained by titrated volume replacement. Lactate, ScvO2 and PDR(ICG) were measured again after 2 h. In both the groups, the mean arterial pressure and heart rate as well as lactate levels and ScvO2 did not change significantly. Although there was a slight but not significant decrease of PDR(ICG) in patients with lumbar EAA (from 25.9 +/- 7.68 to 23.2 +/- 5.90; NS), thoracic EAA resulted in a significant increase of PDR(ICG) (from 21.3 +/- 5.13 to 24.0 +/- 6.66; P < 0.05) for the group mean, but with substantial variability in individual patients in the lumbar EAA group. Liver perfusion was increased with thoracic but not lumbar EAA after major abdominal surgery in most patients. PDR(ICG) allows assessment of individual changes of liver blood flow due to therapeutic intervention, for example, EAA.

Progress in clinical pharmacology over the last 20 years.

Progress in clinical pharmacology over the last 20 years.

High Feed Intake Increases Liver Blood Flow and Metabolism of Progesterone and Estradiol-17β in Dairy Cattle

Increased liver blood flow (LBF) resulting from elevated feed intake in lactating dairy cows may increase steroid metabolism. Continuous infusion of bromosulphthalein (BSP; specifically metabolized in liver) was used to measure LBF. Similarly, progesterone (P4) and estradiol-17β (E2) were administered by continuous infusion. Circulating concentrations at steady state were used to calculate the metabolic clearance rate (MCR) of BSP, P4, and E2. Experiment 1: Variation in LBF was determined in thee nonlactating and four lactating cows over 3 d at 3 to 5h after feeding. Coefficients of variation ranged from 14 to 31% among cows within day and from 4 to 8% within cows across days. Experiment 2: Six nonlactating cows were used in a 3 x 3 Latin-square design with three feed regimens: no feed, 0.5 maintenance diet (M), and 1.5M. Experiment 3: Eight lactating cows were used in a 4×4 Latin-square design with four feed regimens: no feed, 0.5M, 1.5M, and 2.2M. In experiments 2 and 3, LBF and MCR of P4 increased immediately after feed consumption and increases persisted longer at higher intakes. The LBF reached a maximum at 2h after feeding and MCR of P4 reached maximum at 3h after feeding with a positive correlation (r = 0.92) between LBF and MCR for P4. Experiment 4: A crossover design was used to determine MCR of E2 in unfed or full-fed lactating dairy cows. The MCR of E2 increased immediately after feeding and stayed elevated throughout the 4.5-h infusion period. Thus, LBF and steroid metabolism were acutely elevated by feed consumption in lactating and nonlactating cows. Higher rates of LBF and steroid metabolism in lactating than in nonlactating cows may indicate chronic effects of higher feed intakes as well.

Glutamine Metabolism in Sepsis and Infection

Severe infection causes marked derangements in the flow of glutamine among organs, and these changes are accompanied by significant alterations in regional cell membrane transport and intracellular glutamine metabolism. Skeletal muscle, the major repository of glutamine, exhibits a twofold increase in glutamine release during infection, which is associated with a significant increase in endogenous glutamine biosynthesis. Despite an increase in glutamine synthetase activity in skeletal muscle, the intracellular glutamine pool becomes depleted, indicating that release rates exceed rates of synthesis. Simultaneously, the circulating pool of glutamine does not increase, indicating accelerated uptake by other organs. The liver appears to be the major organ of glutamine uptake in severe infection; studies in endotoxemic rodents have shown net hepatic glutamine uptake to increase by as much as 8- to 10-fold. This increase is due partially to increases in liver blood flow, but also to a three- to fourfold increase in hepatocyte System N activity in the liver. Cytokines and glucocorticoids mediate the increased uptake of glutamine by the liver in septic states as well as other compounds. Sepsis does not appear to induce an increase in System N gene expression, indicating that the increase in hepatic glutamine transport observed during severe infection is probably regulated at the protein level. The bowel displays a decrease in glutamine utilization during sepsis, a response that may be related to the decrease in circulating insulin-like growth factor-1 (IGF-1) levels that is characteristic of sepsis. Recent studies suggest that IGF-1 has a direct effect on stimulating glutamine transport across the gut lumen and thus may represent a therapeutic avenue for improving gut nutrition during severe infection. The cells of the immune system (lymphocytes, macrophages) are also major glutamine consumers during inflammatory states in which cell proliferation is increased. Under these conditions, glutamine availability can become rate limiting for key cell functions, such as phagocytosis and antibody production.

Effects of dobutamine on hepato-splanchnic hemodynamics in an experimental model of hyperdynamic endotoxic shock.

Dobutamine infusion has been proposed to increase splanchnic blood flow in septic conditions, but its' effects on liver blood flow and metabolism have not been well defined. We investigated the effects of dobutamine on liver blood flow, metabolism, and pathology in a canine hyperdynamic endotoxic shock model. Twenty-one dogs were anesthetized and paralyzed. After the administration of 2 mg/kg endotoxin, normal saline was infused to restore the pulmonary artery-occluded pressure to 10 mmHg. The dogs were then randomized to receive fluids either alone (n = 7) or combined with a dobutamine infusion at a rate of 5 (n = 7) or 10 microg/kg per min (n = 7). After initial fluid resuscitation, cardiac index (CI) increased from 152+/-48 to 386+/-97 mL/kg per min (P < 0.01) and then slightly decreased with time in the control group, but further increased to 458+/-54 mL/kg per min (P< 0.05) and remained elevated in the group treated with 5 microg/kg per min of dobutamine. Portal vein and hepatic arterial blood flows followed a similar course and increased with fluid resuscitation. Both decreased with time in the control group, but further increased in the dobutamine-treated animals. Liver oxygen delivery (DO2liv) increased with fluids from 2.2+/-2.4 to 3.8+/-1.9 mL/kg per min (P < 0.01) and further increased in the dobutamine-treated animals to 4.1+/-1.2 mL/kg per min. This was associated with an increase in liver oxygen uptake from 1.6+/-1.6 to 2.9+/-1.1 mL/kg per min with fluid resuscitation and a further increase to 4.3+/-1.5 mL/kg per min with dobutamine administration. Lactate consumption and hepatic vein oxygen saturation increased with initial fluid resuscitation and then decreased with time in the control group, but not in the dobutamine-treated animals. Increasing the dose of dobutamine to 10 microg/kg per min did not alter this response. At the end of the experiment, liver tissue samples were obtained for microscopic studies. The histological lesions seen in the control group were unaffected by dobutamine. In conclusion, dobutamine increases liver blood flow and metabolism, but does not affect microscopic findings in this hyperdynamic endotoxic shock model.

Effect of Metoprolol and Verapamil Administered Separately and Concurrently after Single Doses on Liver Blood Flow and Drug Disposition

Nine healthy males participated in a double-blind, placebo-controlled, randomized, crossover study to determine the effects of verapamil and metoprolol administered alone and concurrently on blood flow through the hepatic artery and portal and hepatic veins and to detect a possible drug interaction between the two agents. Single oral doses of placebo/placebo, metoprolol (50 mg)/placebo, verapamil (80 mg)/placebo, or verapamil/metoprolol were separated by at least 14 days. Liver blood flow through individual hepatic vessels was measured up to 8 hours after dosage administration using a duplex Doppler ultrasound technique. Cardiac output, heart rate, blood pressure, stroke volume, and total peripheral resistance were measured for 3 hours after drug doses were given. In 5 subjects, pharmacokinetic parameters for total drug as well as S- and R-enantiomers were also measured. Verapamil given alone caused a rapid and intense increase in liver blood flow (hepatic artery = 50%, portal vein = 42%, hepatic vein = 55%) 0.75 to 1 hour after administration because of a decrease in total peripheral resistance and an increase in heart rate, stroke volume, and cardiac output. Metoprolol given alone caused a slow but prolonged decrease in liver blood flow (maximum decrease: hepatic artery = -54%, portal vein = -21%, hepatic vein = -27%) 4 hours after administration because of a decrease in heart rate and cardiac output. When the two agents were given together, a composite of the changes noted after separate administration was noted: a brief peak increase in liver blood flow at 0.33 to 1 hour followed by a slow, prolonged decrease that reached its maximum decline 4 to 5 hours postdose. During the combined phase, metoprolol and its enantiomers had an increased AUC and Cmax, while verapamil and its enantiomers had an increased AUC and t1/2. These pharmacokinetic changes were consistent with the magnitude and time course of liver blood flow changes through the hepatic artery and portal or hepatic veins.

Effective therapy for hepatic M. Osier with systemic hypercirculation by ligation of the hepatic artery and subsequent liver transplantation

Abstract Hereditary hemorrhagic teleangiectasia, or M. Osier (Osler-Weber-Rendu disease), is an autosomal dominant, systemic fibrovascular dysplasia. This may lead to increased liver blood flow from arteriovenous fistulas. A 45-year-old woman with a known M. Osier was admitted for liver transplantation. On admission, exertional dyspnea was the predominant symptom. Radiological investigations revealed multiple intrahepatic arteriovenous fistulas and consecutive high-output heart failure. Laboratory findings revealed remarkably elevated bilirubin and alkaline phosphatase. To alleviate the high-output cardiac failure, the hepatic artery was ligated. Fourteen months later, the patient presented again with increased levels of bilirubin and recurrent bleeding episodes from esophageal varices grade IV. The patient underwent liver transplantation and post-transplant recovery was excellent. A hyperdynamic circulatory state due to a hepatic M. Osier has been treated in several cases by ligation or embolization of the hepatic artery. This procedure, however, is recommended only for patients with normal liver function and carries a considerable risk of bile duct necrosis.

ONO-5046, an elastase inhibitor, attenuates liver mitochondrial dysfunction after endotoxin.

To investigate the effect of ONO-5046, an elastase inhibitor, on liver mitochondrial dysfunction after endotoxin administration. Prospective, randomized, controlled animal study. Research laboratory. Male Hartley guinea pigs. Endotoxin shock was induced by intravenous infusion of Escherichia coli lipopolysaccharide endotoxin (50 mg/kg). Six guinea pigs were treated with endotoxin and saline. Twenty-four guinea pigs received 5, 10, and 30 mg/kg/hr of ONO-5046 after endotoxin administration. Six guinea pigs received only saline. We measured oxygen uptake in state 3 (substrate and adenosine 5'-diphosphate [ADP]) and state 4 (excess substrate, no ADP), as well as the respiratory control ratio (state 3/state 4), adenosine 5'-diphosphate/oxygen ratio (ADP/O), and arterial ketone body ratio. ONO-5046 was dose dependently effective in liver mitochondrial oxidative phosphorylation, such as oxygen uptake in stage 4, respiratory control ratio, adenosine triphosphate synthesis, ADP/O, and arterial ketone body ratio when ONO-5046 was started 30 mins after endotoxin. The administration of 30 mg/kg/hr of ONO-5046 improved mean blood pressure, which had decreased after endotoxin. ONO-5046 attenuates the endotoxin-induced liver mitochondrial dysfunctions that may be related to increased liver blood flow.

Relationship between cytochrome P-450 induction by rifampicin, hepatic volume and portal blood flow in man.

Induction of hepatic cytochrome P-450-dependent oxidative metabolism is related to an almost identical increase (30%) in both the liver weight and portal blood flow in animals. In humans by contrast, an increased liver blood flow (44%) but no significant increase in liver volume has been reported. Therefore, we studied prospectively the relationship between P-450 induction by rifampicin, hepatic volume and portal blood flow in 10 healthy volunteers. After a pre-treatment phase (day 1 to 7) the 10 volunteers received 600 mg/day of rifampicin from day 7 to 12. The urinary 6-beta-hydroxycortisol output as a measure of oxidative metabolism (CYP3A4) and portal blood flow (pulsed Doppler ultrasound) were determined on days 1, 7, 11 and 13. Hepatic magnetic resonance volumetry was performed on days 1 and 13. Urinary 6-beta-hydroxycortisol output increased in all volunteers (P = 0.0051) from a median of 2.15 micrograms/day/kg (1.8-3.3 micrograms/day/kg) on day 1 to 9.9 micrograms/day/kg (5.7-14 micrograms/day/kg) on day 13. In 9 of 10 volunteers induction by rifampicin was related to an increase (P = 0.0218) in liver volume from a median of 1570 cm3 (1390-1830 cm3) to a median of 1690 cm3 (1420-1860 cm3). The portal flow as assessed by colour Doppler ultrasound did not change significantly between day 1 (median 22 cm/s (15-35 cm/s)) and day 13 (median 19 cm/s (16-39 cm/s)). A fourfold increase of urinary 6-beta-hydroxycortisol output after induction of cytochrome P-450 by rifampicin is associated with a significant but less than 10% increase in human liver volume. No increase of portal perfusion as assessed by Doppler ultrasound could be detected in this study.

The effect of metformin on liver blood flow in vivo in normal subjects and patients with non insulin dependent diabetes

We previously reported that metformin improves insulin-mediated glucose liver metabolism in patients with non insulin dependent diabetes (NIDDM). It is not clear whether this is a direct effect of metformin on liver metabolism or mediated by other mechanisms such as increased liver blood flow. In this respect it has recently been reported that metformin increases hepatic blood flow (HBF) in diabetic rats. The aim of this study was to evaluate whether the administration of metformin is associated with modifications in HBF in humans. Patients affected by NIDDM ( n = 11) and normal subjects ( n = 6) were studied. In the first protocol HBF was investigated in six overweight (BMI 27 ± 2 Kg/m 2) NIDDM patients and six normal subjects (age and BMI matched) already on metformin treatment before and 2 h after the administration of 500 mg metformin. In the second protocol HBF was investigated in obese (BMI 32 ± 1 Kg/m 2) NIDDM patients ( n = 5) in good metabolic control before and after 15 days of metformin at the dose of 1 g daily. HBF was measured by intravenous injection of 3 mCi 99mTc-phytate. In both protocols no significant changes in HBF were observed following metformin administration either in NIDDM patients or normal subjects. No significant differences were observed in HBF between diabetic patients and normal subjects. These data indicate that metformin has no effect on HBF in man. The previously reported improvement of insulin mediated liver metabolism induced by metformin is likely to be a consequence of the direct effect of the drug at hepatocyte level which is independent of HBF modifications

Effects of acute and chronic ethanol administration on hepatic hemodynamics and hepatic oxygen consumption in awake rats

Background/Aims and Methods: We investigated by effects of acute and chronic ethanol administration on hepatic hemodynamics and hepatic oxygen delivery and consumption in awake rats, using the radiolabeled microsphere technique and measurement of oxygen content in blood. Results: Acute oral and intraarterial ethanol administration produced a significant increase in liver blood flow and hepatic oxygen delivery, but resulted in a significant (25–41%) decrease in hepatic oxygen consumption. These changes lasted up to 5 h after ethanol administration. At 24 h, hepatic oxygen consumption was significantly increased by 33% over control values. During withdrawal in rats fed liquid diets containing alcohol for 6 weeks, hepatic oxygen delivery was maintained at the same level as control pair-fed rats, while hepatic oxygen consumption increased by 28%. Further, in abstinent rats, acute ethanol readministration resulted in a 41% increase in hepatic oxygen delivery but a 32% decrease in hepatic oxygen consumption. Conclusions: These findings demonstrate, in awake animals, a biphasic response of hepatic oxygen consumption following acute ethanol administration and an increase in hepatic oxygen consumption following chronic ethanol intake. Furthermore, acute ethanol treatment reduced hepatic oxygen consumption in spite of an increase in hepatic oxygen delivery.

Effects of changing liver blood flow by exercise and food on kinetics and dynamics of saruplase*

To investigate the influence of changes in liver blood flow on the pharmacokinetics and pharmacodynamics of single-chain unglycosylated urokinase-type plasminogen activator. This open, randomized, crossover trial was carried out in the clinical research unit. Infusions of 37.5 mg saruplase and 90 mg indocyanine green were administered over 150 minutes to 10 healthy male volunteers. After 60 minutes the subjects consumed a standardized meal to increase liver blood flow or performed an exercise test (20 minutes) to decrease liver blood flow. Indocyanine green concentrations, total urokinase-type plasminogen activator (u-PA) antigen, two-chain u-PA activity, fibrinogen, total degradation products, alpha 2-antiplasmin, and factor XII-dependent fibrinolytic activity were measured. Blood flow was measured after food intake in a portal vein branch with Doppler echography. The weighted average indocyanine green concentration after exercise was increased by 29% compared with baseline (steady-state concentration) values (95% confidence intervals [CI]: +6%, +56%). After food, the concentration was 27% lower compared with baseline values (95% CI: -35%, -19%), and portal vein flow was increased by a maximum of 103% (95% CI: +71%, +136%). Average maximal concentrations of u-PA antigen after exercise were increased by 130 ng/ml compared with baseline concentrations (95% CI: +65, +195 ng/ml) and, unexpectedly, 156 ng/ml higher after food (95% CI: +59, +253 ng/ml). Although not significant, an increase in average u-PA antigen concentration compared with baseline values was detected after both exercise (7%) and food (13%). This tendency toward a larger effect after food compared with the effect after exercise was reflected by minor changes in the pharmacodynamics. u-PA plasma concentrations were increased by reduced liver blood flow induced by exercise. Food intake produced an unexpected increase in u-PA concentrations despite increases in liver blood flow.

Laser Doppler imaging for the assessment of liver perfusion during transplantation

Objective: Adequate revascularization is one of the essential prerequisites for successful liver transplantation. At present, there are no accurate methods for assessing perfusion of the liver after grafting. The laser Doppler imager is a novel application of Doppler for the measurement of microvascular blood flow in superficial tissues. The technique depends on monochromatic light back-scattered from a tissue being spectrally broadened due to the Doppler shift caused by moving red blood cells. We have investigated the use of the laser Doppler imager for assessing liver blood flow following transplantation.Methods: Liver perfusion was mapped using the laser Doppler imager during orthotopic liver transplantation in two patients.Results: In both patients, the tissue perfused well after revascularization (mean blood flow of 4.09 +/- 1.48 volts, number of spatial samples = 2215). There was a 10% regional variation in blood flow on the surface of the left lobe of the liver. In one of the patients, the splenic artery was clamped which resulted in an increase in liver blood flow of 9.3% from a mean flow of 4.05 +/- 0.81 to 4.43 +/- 0.70 volts.Conclusion: The laser Doppler imager may have an important role in assessing organ revascularization during liver transplantation.

Acute effects of partial hepatectomy on liver blood flow in the jaundiced rat

The aim of this study was to define the effects of hepatic resection on liver blood flow and portal pressure in the presence of obstructive jaundice. Liver blood flow and portal pressure were measured in 17 jaundiced animals (5 days bile duct ligation) and 16 control animals. A 70% liver resection with or without hepatic artery ligation was performed in the control animals. On day 5, the animals underwent a second operation. Hepatic artery ligation alone was performed in a group of control animals. In jaundiced rats there was a decrease in liver blood flow (1.24 +/- 0.23 ml/min per g vs. normal 1.91 +/- 0.38 ml/min per g, P < 0.01) and an increase in portal pressure (11.2 +/- 3.47 mmHg vs. normal 6.93 +/- 1.01 mmHg, P < 0.01). After partial hepatectomy, a significant increase in liver blood flow was observed in controls (2.44 +/- 0.74 ml/min per g, P < 0.01) but not in jaundiced rats. Hepatic artery ligation did not affect blood flow or portal pressure either before or after resection. Small but significant portal-systemic shunting was found in all jaundiced rats (2.19 +/- 2.1% vs. 0.026 +/- 0.015%, P < 0.05). These results demonstrate that partial hepatectomy results in a significant increase in total liver blood flow. Acute cholestasis appears to prevent this increase. Even in the early stages of obstructive jaundice in the rat, there were signs of portal-systemic shunts.

Variability in the pharmacokinetics of nisoldipine as caused by differences in liver blood flow response.

We investigated whether the effect of nisoldipine on liver blood flow depends on its route of administration. Ten healthy subjects took nisoldipine I.V. (infusion) and orally (without and with sotalol pretreatment). Pharmacokinetics of nisoldipine was assessed and liver blood flow (ICG clearance) was measured before dosing and at the end of the infusion or during absorption. During I.V. infusion the ICG plasma clearance increased by only 14%, whereas the increase was 60% during absorption of nisoldipine. Nisoldipine increases liver blood flow considerably only during the absorption phase. A positive correlation was found between the increase in liver blood flow during absorption and the systemic availability of nisoldipine, suggesting that the differences in liver blood flow response to nisoldipine substantially contribute to the variability in pharmacokinetics of the drug.