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Hepatic Uptake (hepatic + uptake)
Selected AbstractsCMR 2005: 1.03: Analysis of hepatic uptake of anionic magnetic nanoparticlesCONTRAST MEDIA & MOLECULAR IMAGING, Issue 2 2006E. Lee [source] Biliary physiology and disease: Reflections of a physician-scientist,HEPATOLOGY, Issue 4 2010Gustav Paumgartner A review is presented of Gustav Paumgartner's five decades of research and practice in hepatology focusing on biliary physiology and disease. It begins with studies of the excretory function of the liver including hepatic uptake of indocyanine green, bilirubin, and bile acids. The implications of these studies for diagnosis and understanding of liver diseases are pointed out. From there, the path of scientific research leads to investigations of hepatobiliary bile acid transport and the major mechanisms of bile formation. The therapeutic effects of the hydrophilic bile acid, ursodeoxycholic acid, have greatly stimulated these studies. Although ursodeoxycholic acid therapy for dissolution of cholesterol gallstones and some other nonsurgical treatments of gallstones were largely superseded by surgical techniques, ursodeoxycholic acid is currently considered the mainstay of therapy of some chronic cholestatic liver diseases, such as primary biliary cirrhosis. The major mechanisms of action of ursodeoxycholic acid therapy in cholestatic liver diseases are discussed. An attempt is made to illustrate how scientific research can lead to advances in medical practice that help patients. (HEPATOLOGY 2010:51:1095,1106.) [source] Uptake and Dispersion of Metformin in the Isolated Perfused Rat LiverJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000CHEN-HSI CHOU Although metformin is a widely used oral antihyperglycaemic, the exact mechanisms of its cellular uptake and action remain obscure. In this study the hepatic extraction and disposition kinetics of metformin were investigated by use of an isolated in-situ rat liver preparation. The liver was perfused in single-pass mode with protein-free Krebs bicarbonate medium at a flow rate of 20mLmin,1. During constant infusion with 1 mgL,1 metformin hydrochloride the hepatic uptake of metformin approached equilibrium within 10 min. The steady-state availability, F, determined from the ratio of outflow concentration to input concentration, was 0.99±0.02 (mean±s.d., n=4). The outflow profile of metformin resulting from a bolus injection of 25 ,g into the portal vein, had a sharp peak then a slower declining terminal phase. The mean transit time (MTT; 49.5±14.5, n = 6) and normalized variance (CV2; 4.13±0.05) of the hepatic transit times of metformin were estimated by numerical integration from the statistical moments of the outflow data. The volume of distribution of metformin in the liver (1.58±0.28 mL (g liver),1) was estimated from its MTT. The volume of distribution is greater than the water space of liver, indicating that metformin enters the hepatic aqueous space and becomes distributed among cellular components. The magnitude of CV2 for metformin is greater than for the vascular marker sucrose, suggesting that distribution of metformin into hepatic tissue is not instantaneous. In conclusion, hepatic uptake of metformin is rate-limited by a permeability barrier. Although metformin is accumulated in the liver, the organ does not extract it. [source] Effect of recombinant porcine somatotropin (rpST) on drug disposition in swineJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2010J. C. KAWALEK Kawalek, J.C., Howard, K.D. Effect of recombinant porcine somatotropin (rpST) on drug disposition in swine. J. vet. Pharmacol. Therap.33, 69,75. Treatment of pigs with recombinant porcine somatotropin (rpST) causes a marked increase in feed utilization with increased weight-gain over untreated controls. Physiological parameters such as creatinine clearance were increased by rpST treatment. Clearance of drugs eliminated by hepatic extraction, like indocyanine green (ICG), were also increased by rpST treatment. However, clearance of intravenous (i.v.)-dosed propranolol (PPL) was not affected by rpST treatment and data from oral (p.o.) - dosing was inconclusive because of the low bioavailability, probably because of a high first-pass effect. The very low oral bioavailability indicates that intestinal metabolism of PPL is probably quite high. Analysis of urinary metabolites indicated production of the two phenolic isomers, but there was no metabolite corresponding to N-dealkylase activity; although the latter metabolite could have been eliminated in the bile with subsequent fecal elimination. PPL was an excellent in vitro substrate for measuring hepatic DME activity in vitro; two phenolic and one N-dealkylated metabolite were formed. The overall conclusions regarding this study must be that the effects of rpST on drug bioavailability and elimination were equivocal. As ICG and creatinine clearances were both increased significantly, one cannot rule out the probability that rpST would increase drug elimination in pigs as a result of increased hepatic uptake and/or renal clearance. One can only speculate that clearance of concurrently administered drugs would be increased. This would reduce residue levels, but it might also reduce efficacy. [source] Genetic cholestasis, causes and consequences for hepatobiliary transportLIVER INTERNATIONAL, Issue 5 2003Peter L. M. Jansen Abstract: Bile salts take part in an efficient enterohepatic circulation in which most of the secreted bile salts are reclaimed by absorption in the terminal ileum. In the liver, the sodium-dependent taurocholate transporter at the basolateral (sinusoidal) membrane and the bile salt export pump at the canalicular membrane mediate hepatic uptake and hepatobiliary secretion of bile salts. Canalicular secretion is the driving force for the enterohepatic cycling of bile salts and most genetic diseases are caused by defects of canalicular secretion. Impairment of bile flow leads to adaptive changes in the expression of transporter proteins and enzymes of the cytochrome P-450 system involved in the metabolism of cholesterol and bile acids. Bile salts act as ligands for transcription factors. As such, they stimulate or inhibit the transcription of genes encoding transporters and enzymes involved in their own metabolism. Together these changes appear to serve mainly a hepatoprotective function. Progressive familial intrahepatic cholestasis (PFIC) results from mutations in various genes encoding hepatobiliary transport proteins. Mutations in the FIC1 gene cause relapsing or permanent cholestasis. The relapsing type of cholestasis is called benign recurrent intrahepatic cholestasis, the permanent type of cholestasis PFIC type 1. PFIC type 2 results from mutations in the bile salt export pump (BSEP) gene. This is associated with permanent cholestasis since birth. Serum gamma-glutamyltransferase (gamma-GT) activity is low to normal in PFIC types 1 and 2. Bile diversion procedures, causing a decreased bile salt pool, have a beneficial effect in a number of patients with these diseases. However, liver transplantation is often necessary. PFIC type 3 is caused by mutations in the MDR3 gene. MDR3 is a phospholipid translocator in the canalicular membrane. Because of the inability to secrete phospholipids, patients with PFIC type 3 produce bile acid-rich toxic bile that damages the intrahepatic bile ducts. Serum gamma-GT activity is elevated in these patients. Ursodeoxycholic acid therapy is useful for patients with a partial defect. Liver transplantation is a more definitive therapy for these patients. [source] Cesium-133: A potential reporter of the hepatic uptake of contrast agentsMAGNETIC RESONANCE IN MEDICINE, Issue 4 2001Jean-Marie Colet Abstract NMR spectroscopy of intracellularly located 133Cs has been used to monitor the uptake of Gd-EOB-DTPA by the isolated rat liver. As shown by 31P spectroscopy, accumulation of 133Cs ions in hepatocytes does not produce detectable effects on the metabolism. The hepatic internalization of Gd-EOB-DTPA was followed by the paramagnetic relaxation enhancement of the intracellular 133Cs ions, and confirmed by parallel quantitations of Gd and Cs run by inductively coupled plasma (ICP) analysis of liver samples and aliquots of perfusate. The relaxation data significantly underestimate the Gd content, suggesting a potential compartmentation of Cs+ and/or the contrast agent. Magn Reson Med 45:711,715, 2001. © 2001 Wiley-Liss, Inc. [source] Changes in Protein, Carbohydrate, and Fat Metabolism with Aging: Possible Role of InsulinNUTRITION REVIEWS, Issue 1 2000Paolo Tessari M.D. Age is associated with modifications of body composition, i.e., an increase in body fat mass and a decrease in protein mass. Because insulin controls substrate disposal and production, these changes could theoretically be related to changes in either insulin action or secretion on the various substrates. On the basis of available evidence, insulin action on whole-body amino acid and protein metabolism seems not to be impaired in the aged. Decreased synthesis of contractile and mitochondrial proteins in muscle, associated with decreased gene expression, was described in humans. Decreased physical activity apparently represents an important factor responsible for decreased muscle protein synthesis and mass in the elderly. Exercise in the elderly may acutely revert these changes, although its chronic effects are still uncertain. In addition, the possible interaction between insulin and exercise in the maintenance of muscle mass needs to be specifically investigated in aged people. Higher free fatty acid (FFA) absolute flux and oxidation rates were observed in healthy elderly subjects in both the fasting state and following hyperinsulinemia, but not when normalized over fat mass. This suggests that FFA kinetics reflect the established changes in fat mass. Insulin sensitivity on glucose metabolism is usually normal in the aged, despite subtle impairments in insulin secretion, hepatic uptake, and onset of action. Finally, data support the operation of the Randle cycle (i.e., inverse relationships between fat and glucose oxidation) in the elderly [source] Effect of macrolide antibiotics on uptake of digoxin into rat liverBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2007Suwako Ito Abstract The objective of this study was to examine the effect of macrolide antibiotics, clarithromycin, erythromycin, roxithromycin, josamycin and azithromycin, on the hepatic uptake of digoxin. The uptake of [3H]digoxin was studied in rats in vivo, using the tissue-sampling single-injection technique, and in isolated rat hepatocytes in vitro. The uptake of [3H]digoxin into rat hepatocytes was concentration-dependent with a Michaelis constant (Km) of 445 nM. All the macrolide antibiotics inhibited the uptake of [3H]digoxin into rat hepatocytes in a concentration-dependent manner. However, clarithromycin did not affect the in vivo hepatic uptake of digoxin in rats. The in vivo permeability,surface area product of digoxin for hepatic uptake (PSinf) was estimated to be 12.5 ml/min/g liver from the present in vitro data, which is far larger than the hepatic blood flow rate (1.4 ml/min/g liver). Macrolide antibiotics at clinically relevant concentrations inhibit digoxin uptake by rat hepatocytes in vitro, but not in vivo, probably because hepatic uptake of digoxin in rats is blood flow-limited. Clinically observed digoxin,macrolide interaction in humans could be due to macrolide inhibition of hepatic digoxin uptake, if the uptake is permeation-limited. Copyright © 2007 John Wiley & Sons, Ltd. [source] | ||||||||||