The effect of hyperosmotic solutions on the hepatic blood flow,

Summary. The present study was undertaken in order to measure the effect of hyperosmotic solutions on portal and hepatic blood flow. In five anaesthetized pigs without arterial blood supply to the liver, portal blood flow rate was measured (electromagnetic flowmeter) during 5 min lasting intravenous infusions of hyperosmotic galactose (50%, 84–100 ml) and mannitol (25%, 100 ml), with physiological saline (100 ml) as control. Portal blood flow increased to a peak value of (39% [P= 0–06] galactose and 37%, [P= 0–06], mannitol) soon after stop of the hyperosmotic infusion. For galactose the change ended somewhat earlier than for mannitol. Saline induced a minor increase (15%). Similarly, increments of, on average, 144% of the hepatic blood flow rate was seen in six patients with cirrhosis, following infusion of hyperosmotic galactose, the increase being more pronounced than in the pigs. The causes for these osmotic effects are not known, but they have to be taken into consideration in studies of the portal and hepatic blood flow.     

The human drug metabolizing cytochromes P450

The superfamily of heme-thiolate proteins known as the cytochromes P450 is responsible for the oxidative metabolism of the majority of drugs. Thus, the phenotypes of individuals with respect to their levels of catalytically active cytochromes P450 determines to a large part the substantial interindividual variation observed in the metabolic clearance of drugs. Over the past 10 years 15 different human cytochromes P450 involved in drug metabolism have been isolated and characterized to varying degrees. This brief review discusses the characterization of these cytochromes P450 and how this knowledge has been used by the pharmaceutical industry to aid in the development of new drugs.     

Calot三角的应用解剖学

本对50例成年尸体Calot三角的形状，内容和位置关系作了调查，并进行了讨论，尤其是对于胆囊动脉在Calot三角内的有关情况作了探讨。     

Hepatic injury and drug metabolism in patients with alpha-methyldopa-induced liver damage

Summary The clinical picture and drug metabolism in 36 consecutive patients with alpha-methyldopa — induced hepatic injury were investigated. The diagnosis was based on case history and biochemical, histological and follow-up studies after withdrawal the drug. Alpha-methyldopa-induced liver damage was found to occur in two phases, acutely within months and chronically within years after beginning treatment. Differences were also found in clinical symptoms and the results of liver tests on the patients if they were divided on the basis of the time factor. Drug metabolism was impaired in patients with alpha-methyldopa-induced liver damage, as indicated by low cytochrome P-450 level in liver biopsies and prolonged antipyrine elimination rate from plasma. Disappearance of the symptoms and normalisation of the liver tests after drug withdrawal occurred faster in patients with an acute type of hepatotoxicity than in subjects with delayed onset of the symptoms. The occurrence of hepatotoxicity in four members of a family suggests a genetic disposition to alpha-methyldopa-induced hepatic injury. The occurrence of two phases of liver damage suggests that a possible mechanism for acute hepatotoxicity might be an allergic reaction to metabolic intermediates produced during breakdown of alpha-methyldopa in the liver. For cases of delayed onset the cause might be increasing damage to microsomal liver protein due to covalent binding during long-term exposure to the drug.     

Histological changes in the liver and indices of drug metabolism in alcoholics

Summary The drug metabolizing capacity of the liver was investigated in 27 consecutive alcoholics by comparison of in vivo (antipyrine kinetics) and in vitro (cytochrome P-450) indices of drug metabolism with quantitative histological determinations of fat, trabeculae and non-fatty parenchyma in liver biopsies, and with biochemical liver function tests. The reduced amount of hepatic parenchyma in the biopsies was related to diminished drug metabolizing capacity, both in vivo and in vitro. The accumulation of fat alone did not significantly alter the kinetics of antipyrine, although it was associated with reduced cytochrome P-450 content. The replacement of parenchyma by fibrous tissue resulted in a decrease both in antipyrine clearance rate and cytochrome P-450 content. There was a logarithmic correlation between the kinetic parameters of antipyrine and cytochrome P-450 in the entire series, whereas a linear relationship was found in the alcoholic subjects in the various diagnostic groups. A non-linear relationship was also found between biochemical liver function tests and the in vivo and in vitro indices of drug metabolism. The results demonstrate that drug metabolizing capacity in alcoholics is related to ethanol-induced changes in the liver. quantitative evaluation of hepatic parenchymal changes, together with tests of the functional capacity of the liver, might be of significance value in predicting the ability of alcoholics to metabolize drugs.     

A theoretical examination of the effects of gut wall metabolism,hepatic elimination,and enterohepatic recycling on estimates of bioavailability and of hepatic blood flow

A model including two eliminating compartments (the liver and the gastrointestinal mucosa) and a noneliminating compartment (the blood or central compartment) was developed to predict the effects of hepatic elimination, gastrointestinal mucosal metabolism, and the occurrence of enterohepatic recycling of a drug and its metabolites on the area under the blood concentrationtime curve (AUC). Several limiting cases where complete absorption or complete or nonexistent enterohepatic recycling of a drug and its metabolite occurred were only considered. Under linear kinetic conditions, the occurrence of hepatic elimination and enterohepatic recycling of a drug and its metabolite in the absence of intestinal mucosal metabolism should affect only the area under the curve and not the availability for both the intraperitoneal and the oral dose. In the presence of intestinal mucosal metabolism, the area under the curve should change with different routes of administration; a larger area, hence a higher availability, should occur after intraperitoneal administration than after oral administration of the drug. For a drug which is eliminated solely by the liver, apparent hepatic flow can be estimated by the dose divided by the difference in the area under the curve for an intravenous dose and the area under the curve for the same intraperitoneal or oral dose. In the absence of gastrointestinal mucosal metabolism, the presence of enterohepatic recycling of a drug and its metabolite should not affect the estimation of apparent hepatic blood flow. However, when gastrointestinal mucosal metabolism is present, there should be an overestimation of hepatic flow when AUC_i.p. and AUC_i.v. are used and a slight underestimation of hepatic flow when AUC_i.v. and AUC_p.o. are used.     

A Detoxification Scheme for Liver Assist Utilizing Plasmapheresis, Bioincompatible Sorbents and Dialysis

The rationale behind the design of a sorbent-based detoxification system for use as a liver assist is presented. A membrane-based plasmapheresis system giving high plasma flows (greater than 40 ml/min) with maximum transmission of albumin makes this concept feasible.     

Effects of liver ischemia on hepatic protein synthesis in vitro and in vivo

When an in vitro system is used to study the influence of ischemia on hepatic protein synthesis, an important question is whether alterations observed in vitro reflect changes in vivo. In the present study the effects of liver ischemia on protein synthesis were investigated in rats both in vitro and in vivo. Liver ischemia was induced by hepatic artery ligation. Protein synthesis in vitro was determined from leucine incorporation into proteins in liver slices incubated in a medium containing ¹⁴C-leucine (0.5 mmol/l) and in vivo from leucine incorporation into hepatic proteins after intraportal injection of a tracer dose of ¹⁴C-leucine. Leucine incorporation rate in non-ischemic liver was 0.16 pmol * g pror¹ h-¹ in vitro and 19.6 μmol g prot-¹. h^-1 in vivo. After hepatic artery ligation protein synthesis in vitro was reduced by about 60% and in vivo by about 80%. Thus, the relative changes were of the same magnitude in vitro and in vivo. This indicates that an in vitro system can be used to evaluate the effects of liver ischemia on hepatic protein synthesis.     

Studies of lipoprotein metabolism in a patient with fish-eye disease

In the rare familial disorder fish-eye disease, hypertriglyceridaemia is associated with elevated levels of very-low-density lipoprotein (VLDL) and enrichment of low-density lipoprotein (LDL) with triglyceride. The kinetic basis of the dyslipoproteinaemia was investigated by studying the metabolism of the apolipoprotein-B moeity of VLDL, intermediate-density lipoprotein (IDL) and LDL in a 68-year-old woman with this condition. The major kinetic abnormality was a pronounced reduction in the rate of fractional conversion of VLDL-B to IDL-B and of IDL-B to LDL-B, suggesting that the dyslipoproteinaemia represents accumulation in plasma of partly degraded products of VLDL metabolism. This kinetic disorder has features in common with type-III hyperlipoproteinaemia. In studies in vitro no defect in the enzyme, activator or substrate components of the lipoprotein lipase or hepatic lipase systems was observed.