Changes In Hepatic Blood Flow Research Articles

Changes in hepatic blood flow in patients with comorbidity of chronic obstructive pulmonary disease and vitamin B12 deficiency anemia

Changes in hepatic blood flow in patients with comorbidity of chronic obstructive pulmonary disease and vitamin B12 deficiency anemia

Hepatic perfusional changes on CT and MRI: a radiology primer.

Hepatic perfusional changes are common in response to, or as a result of, a multitude of pathological processes. These can be neoplastic, inflammatory, fibrotic, or ischemic in origin, to name a few. The liver, having a dual blood supply, is a unique organ to study using contrast-enhanced CT and MRI imaging due to its varied appearance on multiphasic imaging. Knowledge of the CT and MRI appearance of hepatic perfusional changes, in addition to the clinical presentation, can often result in an accurate differential diagnosis. Many of the conditions that cause these changes in hepatic blood flow result in similar appearances on imaging. As a result, it is important that radiologists be aware of common pitfalls when dealing with hepatic perfusional changes to prevent misdiagnosis or delayed diagnosis. As such, this review will focus on some of the various causes of hepatic perfusional changes and how to accurately identify and diagnose them based on their CT and MRI appearance.

Changes in Hepatic Blood Flow and Liver Function during Closed Abdominal Hyperthermic Intraperitoneal Chemotherapy following Cytoreduction Surgery.

Background The increase in intra-abdominal pressure (IAP) during closed abdominal hyperthermic intraperitoneal chemotherapy (HIPEC) leads to major haemodynamic changes and potential organ dysfunction. We investigated these effects on hepatic blood flow (HBF) and liver function in patients undergoing HIPEC following cytoreductive surgery and fluid management guided by dynamic preload indices. Methods In this prospective observational clinical study including 15 consecutive patients, we evaluated HBF by transesophageal echocardiography and liver function by determination of the indocyanine green plasma disappearance rate (ICG-PDR). Friedman's two-way analysis of variance by ranks and Wilcoxon signed-rank test were performed for statistical analysis. Results During HIPEC, HBF was markedly reduced, resulting in the loss of any pulsatile Doppler flow signal in all but one patient. The ICG-PDR, expressed as median (interquartile 25–75), decreased from 23 (20–30) %/min to 18 (12.5–19) %/min (p < 0.001). Despite a generous crystalloid infusion rate (27 (22–35) ml/kg/h), cardiac index decreased during the increased IAP period, inferior vena cava diameter decreased, stroke volume variation and pulse pressure variation increased, lung compliance dropped, and there was an augmentation in plateau pressure. All changes were significant (p < 0.001) and reversed to baseline values post HIPEC. Conclusion Despite optimizing intravenous fluids during closed abdominal HIPEC, we observed a marked decrease in HBF and liver function. Both effects were transient and limited to the period of HIPEC but could influence the choice between closed or open abdominal cavity procedure for HIPEC and should be considered in similar clinical situations of increased IAP.

Nonalcoholic fatty liver with a hepatic arterial buffer response strongly associated with future metabolic disease.

A change in hepatic blood flow caused by the hepatic arterial buffer response (HABR) occurs as fatty liver disease progress. The aim of this longitudinal cohort study was to investigate whether fatty liver with the HABR induces metabolic disorders. In 2009 and 2010, 494 (89.5%) participants were enrolled. The median follow‐up duration was 5.0 (interquartile range, 3.9‐6.0) years. The hazard ratios of fatty liver with the HABR for incident metabolic disorders were assessed by Cox proportional hazard models. A non–fatty liver group (non‐FL group, hepatorenal echo intensity ratio <1.12), a fatty liver without portal hypertension (FL group, hepatorenal echo intensity ratio ≥1.12 and ratio of the maximal blood velocity in the right hepatic artery to maximal blood velocity in the right portal vein <3.1) group, and a fatty liver with portal hypertension (FL‐HABR group, hepatorenal echo intensity ratio ≥1.12 and ratio of the maximal blood velocity in the right hepatic artery to maximal blood velocity in the right portal vein ≥3.1) group were defined based on echo intensity and Doppler ultrasonography. Fatty liver with and without the HABR was significantly associated with the incidence of diabetes on multivariate analysis (non‐FL versus FL group, hazard ratio, 3.36; 95% confidence interval, 1.05‐12.85; FL versus FL with the HABR group, HR, 2.68; 95% confidence interval, 1.28‐6.04). With respect to the incidence of hypertension and dyslipidemia, only FL with the HABR was a significant factor (hypertension, non‐FL versus FL, P = 0.874, FL versus FL‐HABR, P = 0.016, non‐FL versus FL‐HABR, P = 0.023; dyslipidemia, non‐FL versus FL, P = 0.311, FL versus FL‐HABR, P = 0.194, non‐FL versus FL‐HABR, P = 0.038). Conclusion: Fatty liver with the HABR is a high‐risk condition for metabolic diseases. (Hepatology Communications 2017;1:623–633)

Physiologic Reduction of Hepatic Venous Blood Flow by the Valsalva Maneuver Decreases Liver Stiffness.

Liver stiffness increases after intake of food or water, suggesting that hepatic venous blood flow affects the results of elastographic measurements. This study investigated the correlation between in vivo liver stiffness and hepatic blood flow using the Valsalva maneuver for reducing intrahepatic venous blood flow. Intrahepatic changes in venous blood flow were assessed by sonography based on the pulsed wave Doppler velocity, vessel diameter assessment, and blood flow volume measurements in the portal vein and right hepatic vein. Time-harmonic elastography at 7 harmonic driving frequencies (30-60 Hz) was used to measure liver stiffness in the right liver lobe of 15 healthy volunteers. The right hepatic vein diameter, flow volume, and peak pulsed wave velocity decreased during the Valsalva maneuver from mean ± SD values of 8.64 ± 1.85 to 6.55 ± 1.84 mm (P = .002), 0.53 ± 0.23 to 0.37 ± 0.26 L/min (P = .037), and 22.14 ± 4.87 to 17.38 ± 5.41 cm/s (P = .01), respectively. This maneuver decreased liver stiffness in all volunteers by a mean of approximately 13% from 1.71 ± 0.22 to 1.48 ± 0.22 m/s (P = .00006). Our results demonstrate that liver stiffness is sensitive to altered venous blood flow, which is of clinical importance when using elastography for evaluation of portal hypertension. Furthermore, our results indicate that accurate measurement of liver stiffness requires standardized breathing conditions to rule out effects of changes in hepatic blood flow on elastographic findings.

Effects of physical activity upon the liver.

To review the responses of the liver to acute and chronic physical activity and to summarize relationships between physical activity and liver health. A systematic search of HealthStar/Ovid from 1975 through June of 2013, supplemented by articles from other sources. 351 of 8,010 articles identified by HealthStar/Ovid were supplemented by 92 other papers; after focussing, the review was reduced to 435 citations. Prolonged acute exercise reduces hepatic blood flow, stimulating hepatic glycogenolysis, gluconeogenesis and synthesis of some proteins; however, lipid metabolism shows little change. Glutathione depletion suggests oxidative stress. Enzymes affecting carbohydrate metabolism are up-regulated, and lipogenic enzymes are down-regulated. The main triggers are humoral, but hepatic afferent nerves, cytokines, reactive oxygen species, and changes in hepatic blood flow may all play some role. Regular aerobic exercise training improves blood glucose control during exercise by increasing glycogen stores and up-regulating enzymes involved in gluconeogenesis and carbohydrate metabolism. Resistance to oxidant stress is generally increased by training. Lipogenic enzymes are down-regulated, and lipid metabolism is augmented. Modulations of insulin, insulin-like growth factor, glucagon and interleukin-6 may trigger the adaptive responses to training. Cross-sectional and longitudinal studies show that regular exercise can reduce hepatic fat, but the effect on circulating aminotransferases is unclear and the modality and dose of physical activity optimizing health benefits need clarification. Regular moderate physical activity enhances liver health. Adverse functional changes can develop if habitual activity is inadequate, and extremely prolonged competitive exercise may also be harmful, particularly under harsh environmental conditions.

Nonalcoholic Fatty Liver Disease: Portal Hypertension Due to Outflow Block in Patients without Cirrhosis

To prospectively evaluate whether the characteristics of hepatic blood flow change during the early stages of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). All participants provided written informed consent, and the study protocols were approved by the institutional ethics committee. A total of 121 patients with NAFLD that was diagnosed at histologic examination were enrolled. Hepatic blood flow was measured by means of Doppler ultrasonography (US), and the ratio of arterial to portal blood flow (arterioportal ratio) was calculated. Elasticity of the spleen was measured by means of real-time tissue elastography. The elastic ratio was measured as the value in the small splenic vessel divided by the value of the splenic parenchyma. The arterioportal ratio and splenic elasticity were compared in patients with all stages of fibrosis (F0-F4) and with all levels of platelet counts. Correlations among the resistive index of the hepatic artery and that of the splenic artery, the fibrosis 4 index, hepatic elasticity, arterioportal ratio, splenic elasticity, and platelet counts were analyzed. Univariate and multivariate logistic regression analyses were performed. Correlations in patients with platelet counts greater than 200 000/μL also were analyzed. The mean ± standard deviation arterioportal ratio was significantly higher at fibrosis stage 2 (2.4 ± 0.6) than at fibrosis stage 0 (1.8 ± 0.4) in patients with NAFLD (P < .01). Increased splenic stiffness at earlier stages of fibrosis also was observed in patients with NAFLD (fibrosis stage 2, 4.4 ± 2.3; fibrosis stage 0, 3.2 ± 1.9; P < .05). In patients with NAFLD with platelet counts higher than 200 000/μL, pericellular fibrosis was the only significant predictor of hepatic hemodynamic change at multivariate analysis (odds ratio, 7.17; 95% confidence interval: 1.33, 57.13; P = .021). Change in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD because of outflow block in the sinusoidal area.

Changes in Hepatic Blood Flow During Transcatheter Arterial Infusion with Heated Saline in Hepatic VX2 Tumor

This study evaluates the influence of transcatheter arterial infusion with heated saline on hepatic arterial and portal venous blood flows to tumor and normal hepatic tissues in a rabbit VX2 tumor model. All animal experiments were approved by the institutional animal care and use committee. Twenty rabbits with VX2 liver tumors were divided into the following two groups: (a) the treated group (n = 10), which received a 60 mL transarterial injection of 60 °C saline via the hepatic artery; (b) the control group (n = 10), which received a 60 mL injection of 37 °C saline via the hepatic artery. Using ultrasonography, the blood flows in both the portal vein and hepatic artery were measured, and the changes in the hemodynamic indices were recorded before and immediately after the injection. The changes in the tumor and normal liver tissues of the two groups were histopathologically examined by hematoxylin and eosin staining after the injection. After the transcatheter arterial heated infusion, there was a decrease in the hepatic arterial blood flow to the tumor tissue, a significant decrease in the hepatic artery mean velocity (P < 0.05), and a significant increase in the resistance index (P < 0.05). On hematoxylin and eosin staining, there were no obvious signs of tissue destruction in the normal liver tissue or the tumor tissue after heated perfusion, and coagulated blood plasma was observed in the cavities of intratumoral blood vessels in the treated group. The changes in tumor blood flow in the rabbit VX2 tumor model were presumably caused by microthrombi in the tumor vessels, and the portal vein likely mediated the heat loss in normal liver tissue during the transarterial heated infusion.

Реогепатографія з ультразвуковим наведенням електродів як біофізичний метод дослідження печінкового кровотоку

The transcutaneus Rheohepatography with ultrasound electrodes navigation (RUEN) discovered early specifically changes of hepatic blood flow in pts with diffuse hepatic pathology (DHP). It is necessary to use of the Conventional Rheohepatography for screening hepatics hemodynamics disorders in pts with DHP. For more differentiated approach it is necessary to use Doppler imaging of the hepatic blood flow. It is necessary to use the ultrasound electrodes navigation for increase of the self-descriptiveness Rheohepatography and for inclusion ofa maximum quantity hepatic parenchyma between interelectrodes space. As against the classical analysis extremities rheography in interpretation RUEN it is necessary to take into account, that the liver has 2 ways of inflow (proper hepatic artery and portal vein) and 1 way of outflow (hepatic veins running to cava inferior vein).

A Semi-Mechanistic Model to Predict the Effects of Liver Cirrhosis on Drug Clearance

Liver cirrhosis is characterized by a decrease in functional hepatocytes, lowered circulating levels of plasma proteins and alterations in blood flow due to the development of portacaval shunts. Depending on the interplay between these parameters and the characteristics of an administered drug, varying degrees of impaired systemic clearance and first-pass metabolism are anticipated. The Simcyp Population-based ADME Simulator has already been used successfully to incorporate genetic, physiological and demographic attributes of certain subgroups within healthy populations into in vitro-in vivo extrapolation (IVIVE) of xenobiotic clearance. The objective of this study was to extend population models to predict systemic and oral drug clearance in relation to the severity of liver cirrhosis. Information on demographics, changes in hepatic blood flow, cytochrome P450 enzymes, liver size, plasma protein binding and renal function was incorporated into three separate population libraries. The latter corresponded to Child-Pugh scores A (mild), B (moderate) and C (severe) liver cirrhosis. These libraries, together with mechanistic IVIVE within the Simcyp Simulator, were used to predict the clearance of intravenous and oral midazolam, oral caffeine, intravenous and oral theophylline, intravenous and oral metoprolol, oral nifedipine, oral quinidine, oral diclofenac, oral sildenafil, and intravenous and oral omeprazole. The simulated patients matched the clinical studies as closely as possible with regard to demographics and Child-Pugh scores. Predicted clearance values in both healthy control and liver cirrhosis populations were compared with observed values, as were the fold increases in clearance values between these populations. There was good agreement (lack of statistically significant difference, two-tailed paired t-test) between observed and predicted clearance ratios, with the exception of those for two studies of intravenous omeprazole. Predicted clearance ratios were within 0.8- to 1.25-fold of observed ratios in 65% of cases (range 0.34- to 2.5-fold). The various drugs that were studied showed different changes in clearance in relation to disease severity, and a 'one size fits all' solution does not exist without considering the multiple sources of the changes. Predictions of the effects of liver cirrhosis on drug clearance are of potential value in the design of clinical studies during drug development and, clinically, in the assessment of likely dosage adjustment.

Changes in hepatic blood flow during whole body hyperthermia

Purpose: Changes in blood flow distribution are important for heat dispersion and for supportive therapeutic strategies such as simultaneous whole body hyperthermia (WBH) and administration of chemotherapy. The aim of this clinical study was to determine changes in hepatic blood flow during WBH for the treatment of metastatic cancer.Materials and methods: This observational clinical study was part of a phase I/II feasibility study of WBH. WBH was induced using a radiant heat device. Hepatic blood flow was estimated using indocyanine green clearance measurements. The plasma disappearance rate of indocyanine green (PDR-ICG) was recorded in percent/min. We used an invasive thermo-dye-dilution technique to estimate hepatic blood flow, cardiac output, and volume status. Mean arterial blood pressure was also measured invasively. To determine the effects of hyperthermia the measurements were performed at defined temperature points.Results: In 10 of 22 treatments the PDR-ICG fell below normal values during hyperthermia, which represented a significant fall in hepatic blood flow. Cardiac output, volume status, and mean arterial blood pressure did not differ between patients whose liver blood flow was reduced and those whose liver blood flow remained unchanged.Conclusions: We observed distinct reductions in hepatic blood flow during WBH, which suggested a significant redistribution of blood flow away from the core during WBH. This was not mirrored by global circulatory parameters.

Lack of effect of subject posture on intravenous midazolam clearance: implications for hepatic cytochrome P450 3A phenotyping

Intravenous (i.v.) midazolam is used to phenotype hepatic cytochrome P450 (CYP) 3A [1]. Midazolam clearance (CL) is believed to correlate with the intrinsic hepatic CL (CLint) of midazolam and thus acts as a surrogate for hepatic CYP3A activity. Midazolam is a moderate extraction ratio drug [2]. Based on the well-stirred model of hepatic clearance [3], midazolam CL depends on CLintand hepatic blood flow. Subject posture alters hepatic blood flow, is often not controlled during blood sample collection [1], and impacts pharmacokinetic studies [4]. The magnitude of posture-induced blood flow changes has been seen in a study of six subjects. Plasma midazolam CL decreased 48% in an ambulant (sitting/walking) posture compared with a supine posture [5] and suggests that changes in midazolam CL may be dependent on hepatic blood flow and not exclusively CYP3A activity. This study evaluated the effect of subject posture on midazolam CL to confirm previous findings. We quantified posture-induced hepatic blood flow changes with i.v. indocyanine green as a biomarker. Results are published elsewhere [6]. The Institutional Review Board of Bassett Healthcare (Cooperstown, NY, USA) approved the study. Written informed consent was obtained. Healthy adults 18–55 years old who were not on any medications were enrolled. Subjects were randomized to a 7-h supine or ambulant posture. A minimum of 7 days passed between study phases. Subjects maintained strict horizontal bed rest during supine posture. During ambulant posture, subjects were seated for the first 3 h and then allowed to stand, walk, or sit. Sessions began between 06.00 h and 07.00 h to minimize temporal variation [5]. Subjects fasted (except water) overnight and for the duration of each posture. To stabilize hepatic blood flow, subjects were in the assigned posture for 1 h prior to midazolam 0.025 mg kg−1 i.v. (midazolam hydrochloride, 1 mg ml−1 injection, North Chicago, IL, USA) administration. Eight blood samples were obtained over 6 h. Samples were centrifuged and stored at −80°C. Plasma concentrations were analysed by liquid chromatography/mass spectrometry/mass spectrometry as described elsewhere [7]. The linear range of the assay was 0.50–100 ng ml−1, with intra- and interday coefficients of variation of ≤7.9% at 0.75, 7.5 and 75 ng ml−1. Midazolam pharmacokinetics was determined by noncompartmental analysis (WinNonlin v3.1; Pharsight, Cary, NC, USA). Sample size calculations were based on previously published data [5, 8–10]. Using an α= 0.05 and β= 0.20, a sample size of 12 would detect a 25% difference in midazolam CL. Bioequivalence testing was used by calculating the least squares geometric mean ratios (LS-GMR; CLambulant/CLsupine) and 90% confidence intervals (CI). Bioequivalence was concluded if the 90% CIs were within the 80–125% interval. Thirteen (seven female) subjects completed both postures. Plasma midazolam concentrations vs. time are shown in Figure 1. Bioequivalence was observed for the geometric mean midazolam CLs in the supine and ambulant phases (595.6 vs. 565.1 ml min−1; LS-GMR 0.95, 90% CI 0.88, 1.02). Intersubject variation of midazolam CL was small, varying 1.7- and two-fold in the supine and ambulant postures, respectively. The volume of distribution (Vd) decreased 18% in the ambulant posture. The difference in Vd may be due to changes in tissue binding, but for CYP3A phenotyping in healthy adults this change is unlikely to be of clinical significance. Figure 1 Mean ± SD midazolam plasma concentrations vs. time in the ambulant (closed squares) and supine (open circles) postures (n= 13) Studies have observed posture-induced changes in hepatic blood flow of 17–37% for several medications [11, 12]. In the current study, subject posture did not affect midazolam CL. In contrast to the study of Klotz et al. [5], the current study used a smaller midazolam i.v. dose (0.025 vs. 0.075 mg kg−1), had a larger sample size (13 vs. 6), and had subjects remain fasting during the entire sampling period. Food intake increases hepatic blood flow and lasts up to 190 min [13]. We speculate that the small sample size and food intake may have affected midazolam CL in the Klotz et al. study [5]. Neither study reported the exact amount of time during the ambulant posture that subjects were in a sitting, walking and standing posture, and potential differences between subjects and studies may have existed in the amount of time spent in a specific ambulant position. Phenotyping studies using i.v. midazolam as a hepatic CYP3A probe do not need to control for subject posture during blood sample collection. These findings are not applicable when using oral midazolam to phenotype intestinal and hepatic CYP3A activity, as i.v. midazolam exclusively measures hepatic CYP3A.

Dual drug interactions via P-glycoprotein (P-gp)/ cytochrome P450 (CYP3A4) interplay: recent case study of oral atorvastatin and verapamil

To the Editor: While drug interaction is an intriguing subject for a clinical pharmacologist/pharmacokineticist, it may be a nightmare for a medical practitioner who needs to juggle dosing adjustments (if applicable) to ensure safety and efficacy so that a co-prescribed therapy is not compromised. In recent years, the concept of dual drug interaction, especially as it relates to P-gp and CYP3A4, has received considerable attention [1–9]. At the outset, it may appear that both P-gp and CYP3A4 are working in tandem to control the oral bioavailability of xenobiotics as they are absorbed through the oral gastrointestinal cavity. However, there may be challenges and complexities to understanding the nature of pharmacokinetic interaction if co-administered compounds have a profound influence on both transporter and enzymatic systems [10–15]. Additionally, the direction and nature of the interaction may further be confounded by physical and/or physiological variants such as food intake, biliary excretion and enterohepatic recycling of the parent/ key metabolites and changes in hepatic blood flow [16–19]. Statins, a well-established class of HMG-CoA reductase inhibitors, provide the fullest scope for understanding the mechanisms governing the dual inhibitory properties that involve the interplay between transport and enzyme systems [18]. Statins can generally be classified into four groups in terms of metabolism preferences within the CYPP450 system: (1) CYP3A4-dependent: atorvastatin and simvastatin, (2) CYP2C9-dependent: fluvastatin, (3) dual CYP (3A4/2C9)-dependent: cerivastatin, and (4) metabolically stable: pravastatin and pitavastatin. However, regardless of metabolism preferences, transport appears to be important for all statins. In addition to P-gp’s involvement in the efflux phenomenon, hepatic uptake transporter may play an important role in its efficacy as well as in clearance mechanisms [18]. Therefore, it is not surprising that statins are compounds of choice for evaluating dual drug-drug interaction potential with the CYP3A4 enzymatic system and Pgp transport system. In a recently published study, Choi et al. (2008) demonstrated a significant single-dose pharmacokinetic interaction between verapamil and atorvastatin in healthy subjects. Therefore, atorvastatin could hinder the formation of norverapamil, an active metabolite of verapamil, due to the potential inhibition of CYP3A4 isozyme. Additionally, it could further enhance the oral bioavailability of verapamil by sufficiently inhibiting the P-gp efflux pump. Based on the data presented in the paper, it appeared that P-gp inhibition could possibly play a greater role than CYP3A4 inhibition because the extent of exposure to norverapamil was virtually unchanged between the two treatments (250±62 ng·h/mL without atorvastatin vs. 265±49 ng·h/mL with atorvastatin) [1]. One must agree, however, with the authors’ interpretation for the considerable decrease in the metabolic ratio (exposure of norverapamil:exposure of verapamil) with atorvastatin treatment; they believed it was primarily driven by an increase in verapamil exposure as opposed to reduced formation of norverapamil [1]. However, no pharmacokinetic data were gathered in this report to evaluate if the kinetics/ disposition of atorvastin and/or its metabolites changed after the co-administration of verapamil [1]. Previously, it was shown that verapamil co-administration enhances the exposure of simvastatin, presumably by its inhibitory effects on both CYP3A4 and P-gp [20]. As verapamil itself is a widely studied substrate because it can Eur J Clin Pharmacol (2008) 64:1135–1136 DOI 10.1007/s00228-008-0512-8

Intraportal administration of neuropeptide Y and hepatic glucose metabolism

We examined whether intraportal delivery of neuropeptide Y (NPY) affects glucose metabolism in 42-h-fasted conscious dogs using arteriovenous difference methodology. The experimental period was divided into three subperiods (P1, P2, and P3). During all subperiods, the dogs received infusions of somatostatin, intraportal insulin (threefold basal), intraportal glucagon (basal), and peripheral intravenous glucose to increase the hepatic glucose load twofold basal. Following P1, in the NPY group (n = 7), NPY was infused intraportally at 0.2 and 5.1 pmol.kg(-1).min(-1) during P2 and P3, respectively. The control group (n = 7) received intraportal saline infusion without NPY. There were no significant changes in hepatic blood flow in NPY vs. control. The lower infusion rate of NPY (P2) did not enhance net hepatic glucose uptake. During P3, the increment in net hepatic glucose uptake (compared with P1) was 4 +/- 1 and 10 +/- 2 micromol.kg(-1).min(-1) in control and NPY, respectively (P < 0.05). The increment in net hepatic fractional glucose extraction during P3 was 0.015 +/- 0.005 and 0.039 +/- 0.008 in control and NPY, respectively (P < 0.05). Net hepatic carbon retention was enhanced in NPY vs. control (22 +/- 2 vs. 14 +/- 2 micromol.kg(-1).min(-1), P < 0.05). There were no significant differences between groups in the total glucose infusion rate. Thus, intraportal NPY stimulates net hepatic glucose uptake without significantly altering whole body glucose disposal in dogs.

Correlation between Hepatic Tumor Blood Flow and Glucose Utilization in a Rabbit Liver Tumor Model

To prospectively determine the relationship between hepatic tumor blood flow and glucose utilization in vivo by using a combined positron emission tomographic (PET)/computed tomographic (CT) scanner. The animal care and use subcommittee at the University of Western Ontario approved this study. VX2 carcinoma cells were implanted in the livers of eight male New Zealand white rabbits. Functional CT was performed before tumor implantation and every 4 days thereafter. Each examination consisted of two phases: In the first phase, 30-second cine breath-hold scanning was performed with simultaneous injection of 5 mL of contrast material. In the second phase, 4-second cine scanning was performed without breath holding every 10 seconds for 2 minutes. Second-phase CT images were coregistered with first-phase images to eliminate breathing artifacts. The weighted summation of the aortic and portal venous time-attenuation curves was deconvolved against curves from the liver to derive hepatic blood flow (HBF). Five animals underwent fluorine 18 fluorodeoxyglucose (FDG) scanning before and every 8 days after implantation. FDG uptake was measured as standardized uptake value (SUV). Data were analyzed with repeated-measures analysis of variance and the Tukey-Kramer multiple comparison test. Linear regression was used to compare SUV and HBF in tumors and normal tissue. In the hypovascular tumor core, (a) mean HBF decreased from 262 mL.min-1.100 g-1+/-22 (standard deviation) at baseline to 101 mL.min-1.100 g-1+/-62 at the end of the study (P<.05) and (b) mean SUV increased from 2.12 g/mL+/-0.06 to 4.56 g/mL+/-0.73 (P<.05) during the same period. Functional CT in combination with FDG PET can be used to observe changes in HBF and glucose utilization in a growing liver tumor.

Pharmacokinetic variation

Pharmacokinetic variability results from differences between patients in the absorption, distribution, elimination and metabolism of a drug. Thus, a given dose may produce different drug concentration profiles against time in individual patients. The importance of pharmacokinetic variability in any situation depends on the mechanisms normally responsible for distribution and elimination of a particular drug, the possible influence of patient characteristics or co-administered drugs on these mechanisms, and the therapeutic margin of the drug. Gastrointestinal absorption may be slowed by atropine or opiates, or accelerated by metoclopramide, which hastens gastric emptying. Muscle mass is greater and adipose tissue mass smaller in men than in women. Thus, water-soluble drugs have larger distribution volumes in men and lipid-soluble drugs (e.g. diazepam, propranolol) have larger distribution volumes in women. Highly extracted drugs (e.g. propofol, propranolol) with clearance close to hepatic blood flow are sensitive to changes in hepatic blood flow, whereas enzyme induction or inhibition, or changes in protein binding have minimal effect. The opposite is true for low extraction drugs (e.g. phenytoin, warfarin). The clearance of renally excreted drugs is decreased in patients with renal failure. In elderly patients, the usual trend is a decrease in central volume of distribution and clearance. In general terms, drug dosage can be reduced if drug distribution or clearance are decreased, and increased if changes in the opposite direction are anticipated. Changes in central volume of distribution influence peak concentrations obtained, whereas clearance has a greater effect on rate of decline in blood concentration and maintenance dose requirement.

Effects of posture (P) induced changes in hepatic blood flow (HBF) and plasma protein binding (PB) on the clearance (CL) of the intravenous (IV) cytochrome P450 3A (CYP3A) biomarker midazolam (MDZ)

Background Use of IV MDZ as a CYP3A probe assumes MDZ CL accurately reflects hepatic CYP3A activity. Because MDZ is a moderate hepatic extraction drug, P induced changes in HBF and/or MDZ plasma PB may affect MDZ CL. Methods 15 healthy, nonsmoking subjects were randomized to a crossover study of supine or ambulant (sitting, standing, walking) P. Fasting subjects received MDZ 0.025 mg/kg IV push and indocyanine green (ICG) 0.5 mg/kg IV to quantify HBF. 18 plasma samples were collected over 6 hr and analyzed by LC/MS/MS (MDZ), HPLC/UV (ICG), and ultra filtration (free MDZ; protein binding). Least squares geometric mean ratios (LS-GMR) and 90% CIs were compared by P. A paired t-test compared free MDZ concentrations and MDZ free fraction by P. Results 13 subjects (7 women) completed the study. (see Table) Correlation of MDZ CL and ICG CL in supine P was r=0.6 (p≤0.05) and ambulant P was r=0.11 (p=0.72). MDZ free fraction 30 min post MDZ and 3 min post ICG were not related to posture (p>0.05). Total MDZ CL did not correlate to MDZ free fraction (r=0.17; p=0.41). Conclusions P induced changes in HBF were minimal and thus the effect of HBF on MDZ CL was not seen. No relationship was observed between MDZ free fraction and MDZ CL. Clinical Pharmacology & Therapeutics (2005) 77, P33–P33; doi: 10.1016/j.clpt.2004.12.017 GM Supine GM Ambulant LS-GMR 90% CI ICG CL (mL/min) 617.8 605.9 0.98 0.86–1.1 MDZ CL (mL/min) 595.6 565.1 0.95 0.88–1.02 GM (SD) GM (SD) p-value Free MDZ (ng/mL)30 min post MPZ 0.25 (0.2, 0.3) 0.28 (0.21, 0.36) p = 0.07 Free MDZ (ng/mL)3 min post ICG 0.16 (0.13, 0.2) 0.16 (0.12, 0.23) p = 0.81

Effect of early wound excision on changes in plasma nitric oxide and endothelin-1 level after burn injury: an experimental study in rats

The purpose of this study was to evaluate effects of early wound excision on changes in NO and endothelin-1 (ET-1) level in the plasma after extensive burn injury. The effects on vascular permeability and hepatic blood flow (HBF) were also assessed. Male Wistar rats were used for this study. A 30% total body surface area (TBSA) third-degree burn was made on the back. Then animals were divided into four groups. Burn group ( n = 13), burn alone; infusion group ( n = 13), burn injury and fluid resuscitation; early excision group ( n = 13), burn injury, total wound excision at 30 min after the injury followed with immediate allogenic skin graft and fluid resuscitation; and the sham group ( n = 15). The sham group and the early excision group did not show significant changes in the NO and ET-1 level in plasma during experimental period, while the burn group and the infusion group showed significant increase in the NO and ET-1. The early excision group also did not show hypovolemia, and the significant decrease in the HBF. These data suggest that the increased NO and ET-1 in plasma following thermal injury were originated from burned tissue and the removal of these injured tissue has beneficial effect on the vascular permeability and the changes in HBF.

Intraportal nicotine infusion in rats decreases hepatic blood flow through endothelin-1 and both endothelin A and endothelin B receptors

Smoking has been demonstrated to aggravate liver injury. Nicotine, a major pharmacological component of tobacco smoke, affects a multitude of functions. Smoking and nicotine induce synthesis of endothelin (ET)-1. The effect of intraportal infusion of nicotine on hepatic circulation and an involvement of ET-1 and ET receptor in the action of nicotine were investigated in rats. Nicotine (0–100 μg/kg/h) was infused into the portal vein of urethane-anesthetized rats, and changes of hepatic blood flow were evaluated. Intraportal infusion of nicotine dose-dependently decreased hepatic blood flow and increased portal pressure without any alteration of heart rate or arterial blood pressure. This action of intraportal nicotine was completely abolished by pretreatment of ET-1 antibody. Either BQ485 (ET A receptor antagonist) or BQ788 (ET B receptor antagonist) partially reversed the effect of nicotine, and combination of BQ788 and BQ485 completely abolished it. These findings suggest that nicotine inhibits hepatic circulation through ET-1, and ET A and ET B receptor.

Radiofrequency Ablation: Effect of Pharmacologic Modulation of Hepatic and Renal Blood Flow on Coagulation Diameter in a VX2 Tumor Model

To determine whether pharmacologic agents can be used to modulate blood flow in hepatic and renal tumors sufficiently to alter the extent of radiofrequency (RF)-induced coagulation. VX2 tumors (8-15 mm) were implanted in the liver (n = 25) or kidney (n = 8) of 33 New Zealand White rabbits. RF was applied to tumors for 6 minutes with use of conventional electrodes (125 mA +/- 35; 90 degrees C +/- 2 degrees C tip temperature). In the hepatic model, blood flow was modulated with use of halothane, epinephrine, or arsenic trioxide (2-6 mg/kg). Laser Doppler flowmetry was used to quantify changes in hepatic blood flow. Correlation of blood flow with induced coagulation diameter was performed. RF ablation was then performed in a renal model with and without arsenic trioxide. For liver tumors, halothane and arsenic trioxide reduced blood flow to 40.3% +/- 17.8% and 29% +/- 15% of normal, respectively, whereas epinephrine increased blood flow to 207.8% +/- 97.9%. Correlation of blood flow to coagulation diameter was demonstrated (R(2) = 0.40). Coagulation measured 7 mm +/- 1 with epinephrine, 10 mm +/- 1 with normal blood flow, 12 mm +/- 3 with halothane, and 13 mm +/- 3 with arsenic trioxide (P <.04 compared with controls). In the renal model, arsenic trioxide decreased blood flow (44% +/- 16%) and increased coagulation diameter (10.9 mm +/- 1) compared with controls (84% +/- 11% and 7.6 mm +/- 1; P <.01, both comparisons). RF-induced coagulation necrosis in rabbit hepatic and renal tumors is affected by tumor blood flow. Pharmacologic modulation of tumor blood flow may provide a noninvasive way to decrease blood flow during thermally mediated ablation therapy, potentially enabling the creation of larger zones of coagulation necrosis.