Kupffer cell function during the erythocytic stage of malaria.

Background And Aim: Previous studies using isolated perfused rat liver in vivo have suggested that during the erythrocytic phase of malaria infection, overall phagocytosis by Kupffer cells is enhanced. The aim of the present study was to further investigate the individual phagocytic capacity and prostaglandin E(2) (PGE(2)) secretion of isolated Kupffer cells in vitro, and the immunohistochemical characteristics of Kupffer cells in vivo.

Methods: Malaria was induced in male Sprague-Dawley rats (n = 12) by inoculation with parasitized red cells containing Plasmodium berghei.

Differential bidirectional transfer of indinavir in the isolated perfused human placenta.

The protease inhibitor (PI) indinavir may be used in the management of human immunodeficiency virus (HIV) infection during pregnancy. Poor maternal-to-fetal transfer of indinavir has been reported previously, but the mechanisms of transfer remain unknown. The bidirectional transfer of indinavir was assessed in dually perfused, isolated human placentae.

Reduced tubular cation transport in diabetes: prevented by ACE inhibition.

Background: The renal clearance of organic cations is important for the homeostasis of a number of exogenous and endogenous compounds. The organic cation transporters (OCTs) situated on the basolateral surface of proximal tubular cells mediate active cation excretion. Alterations of cation transport may occur in diabetes, although the role of the OCTs has not been previously assessed.

A novel method for determining hepatic sinusoidal oxygen permeability in the isolated perfused rat liver using [15O]O2.

Measurement of hepatic sinusoidal permeability of oxygen and other substrates may help elucidate the mechanisms responsible for impaired liver function in cirrhosis. However studies of sinusoidal oxygen permeability in normal liver and various disease states have been limited due to the considerable technical difficulties involved in the use of standard techniques. We have developed a new method for measuring sinusoidal oxygen permeability in the isolated perfused rat liver that overcomes the difficulties of previous methods by using [(15)O]O(2) and an in-line fluid monitor.

The effect of oxygen supplementation on the arterial ketone body ratio in human cirrhosis.

Background/aims: Data from studies in experimental models have suggested that the impairment of mitochondrial function and altered redox state that occur in cirrhosis may be due to impaired hepatic oxygenation. Since interventions that improve oxygen delivery to hepatocytes may improve mitochondrial functions, we studied the effects of oxygen supplementation on the arterial ketone body ratio (AKBR) in normal volunteers and patients with cirrhosis.

Methods: After a 2-hour fast, ketone bodies were measured in arterial blood taken from patients and controls while breathing room air and then after breathing oxygen via a face mask at 12 liters/min for 60 min.

Hepatic Kupffer cell phagocytotic function in rats with erythrocytic-stage malaria.

Background: In the erythrocytic phase of malaria, Kupffer cells show marked hypertrophy and hyperplasia and are filled with malarial pigment. However, phagocytic function in this state has not been well characterized. The aim of the present study was to use mouse Plasmodium berghei to infect rats with malaria and study the phagocytic function and morphology of Kupffer cells.

Differential inhibition of human CYP1A1 and CYP1A2 by quinidine and quinine.

1. The inhibition of recombinant CYP1A1 and CYP1A2 activity by quinidine and quinine was evluated using ethoxyresorutin O-deethylation, phenacetin O-deethylation and propranolol desisopropylation as probe catalytic pathways. 2.

Neonatal hepatic drug elimination.

After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life.

Right heart failure impairs hepatic elimination of p-nitrophenol without inducing changes in content or latency of hepatic UDP-glucuronosyltransferases.

Congestive heart failure has been shown to affect oxidative drug metabolism, however, there has been little study of its effects on drug conjugation. Using the isolated perfused livers from rats with right ventricular failure (RVF) due to pulmonary artery constriction, we studied the effects of RVF on hepatic elimination of p-nitrophenol (PNP) under controlled flow and oxygen delivery conditions. Hepatic clearance of the drug was found to be significantly impaired in RVF as compared with the sham group (0.

Role of cytochrome P450 2D6 (CYP2D6) in the stereospecific metabolism of E- and Z-doxepin.

The tricyclic antidepressant, doxepin, is formulated as an irrational mixture of E (trans) and Z (cis) stereoisomers (85%: 15%). We examined the stereoselective metabolism of doxepin in vitro, with the use of human liver microsomes, recombinant CYP2D6 and gas chromatography-mass spectrometry. In human liver microsomes over the concentration range 5-1500 microM, the rate of Z-doxepin N-demethylation exceeded that of E-doxepin above 100 microM in two of three livers.

Impaired elimination of propranolol due to right heart failure: drug clearance in the isolated liver and its relationship to intrinsic metabolic capacity.

It is unclear if reduced hepatic drug elimination in congestive heart failure is primarily due to impairment of enzyme function as a result of tissue hypoxia, to the direct effects of hepatic congestion, or to changes intrinsic to the liver, such as reductions in enzyme content and activity. We therefore compared propranolol clearance in perfused rat livers from animals with right ventricular failure (RVF) with that from control animals. Despite the fact that both groups were perfused at comparable flow rates, perfusion pressures, and levels of oxygen delivery, hepatic extraction of propranolol was significantly reduced in RVF livers (0.

Neonatal hepatic propranolol elimination: studies in the isolated perfused neonatal sheep liver.

Using the isolated perfused neonatal sheep liver model, we examined the disposition of propranolol (n = 8, age 0.25-10 days) and compared our findings with our previous study from the perfused near-term fetal sheep liver (Ring JA, et al. 1995.

Stereoselective measurement of E- and Z-doxepin and its N-desmethyl and hydroxylated metabolites by gas chromatography-mass spectrometry.

A stereoselective method of analysis of the antidepressant drug doxepin (DOX, an 85:15% mixture of E-Z stereoisomers), its principal metabolites E- and Z-N-desmethyldoxepin (desDOX) and ring-hydroxylated metabolites in microsomal incubation mixtures is described. DOX and its metabolites were extracted from alkalinised incubation mixtures by either: 9:1 hexane-propan-2-ol (method 1) or 1:1 hexane-dichloromethane (method 2), derivatised with trifluoroacetic anhydride and analysed by GC-MS with selected ion monitoring. Both methods were suitable for the analysis of individual desDOX isomers as indicated by correlation coefficients of > or = 0.

Fetal hepatic drug elimination.

The majority of studies of fetal hepatic elimination have concentrated on the expression and activity of the metabolizing enzymes, but the unique physiologic milieu of the fetal liver should also be considered. The basic structure of the liver is formed by the end of the first trimester. The fetal hepatic circulation differs substantially from that of the adult in that there is an extra input vessel, the umbilical vein, and there is shunting of 30-70% of hepatic blood flow via the ductus venosus.

Conjugation of para-nitrophenol by the isolated perfused neonatal sheep liver.

We examined the metabolism of para-nitrophenol (PNP) in the isolated perfused neonatal sheep liver (n = 8, 0.25-11 days) and compared the findings with our previous data from the perfused near-term fetal sheep liver (Ring, J. A.

Uptake and excretion of sodium taurocholate by the isolated perfused neonatal sheep liver.

We present a model for perfusion of the isolated perfused neonatal sheep liver which allows examination of drug disposition by the intact organ. We studied the disposition of sodium taurocholate (TC) in seven neonatal lambs (ages 2-11 days) and compared the results with earlier data from the perfused fetal sheep liver (Ring, J. A.

Metabolism of dexfenfluramine in human liver microsomes and by recombinant enzymes: role of CYP2D6 and 1A2.

Dexfenfluramine has been widely used as an appetite suppressant in the treatment of obesity. It was recently shown that the apparent non-renal clearance of dexfenfluramine was significantly lower in poor metabolizers than in extensive metabolisers of debrisoquine which suggested the involvement of the polymorphically expressed enzyme, CYP2D6, in dexfenfluramine metabolism. In this study, human liver microsomes and yeast-expressed recombinant enzymes were used to examine dexfenfluramine metabolism in vitro.

A priming dose of propranolol reduces the availability of a subsequent dose in the isolated perfused rat liver preparation.

1. A 50 microL bolus dose containing (+/-)-propranolol hydrochloride (200 microg) and [14C]-sucrose, or antipyrine (2 mg) and [14C]-sucrose, or [14C]-taurocholate sodium was injected into the portal vein of the isolated perfused rat liver preparation and perfusate outflow samples were collected frequently for the next 30 min. After a 20 min washout period this procedure was repeated.

Propranolol elimination by right and left fetal liver: studies in the intact isolated perfused fetal sheep liver.

Propranolol extraction in vivo by the left lobe of the fetal sheep liver is greater than that by the right lobe, and this may be due to the fact that oxygenation of the left lobe is greater than that of the right lobe. To explore this hypothesis, we studied the elimination of (R)-(+)-propranolol (PROP) by right and left lobes of the intact isolated perfused fetal sheep liver model, in which there is equal oxygenation of both liver lobes. After isolation of the liver, near-term fetal sheep livers (n = 11) were perfused (2.

Measurement of dexfenfluramine metabolism in rat liver microsomes by gas chromatography-mass spectrometry.

A specific and useful method was developed for the determination of dexfenfluramine metabolism by microsomal systems utilising GC-MS. The synthesis of two metabolites 1-(3-trifluoromethylphenyl)propan-2-ol ('alcohol') and 1-(3-trifluoromethylphenyl)-1,2-propanediol ('diol') via straightforward routes, were confirmed by MS and NMR spectra. The conditions for extraction from alkalinised microsomal mixtures of the metabolites nordexfenfluramine, 1-(3-trifluoromethylphenyl)propan-2-one ('ketone'), alcohol and diol, their conversion to trifluoroacetate derivatives and analysis by GC-MS-SIM are described.

Effects of acute myocardial infarction on theophylline elimination in rats.

We investigated the effect of acute myocardial infarction (MI) on the hepatic clearance of theophylline in rats using the coronary artery ligation model. After 48 hr of ligation, there were significant changes in left ventricular performance in the MI rats, compared with controls, as indicated by elevated left ventricular end-diastolic pressure, reduced mean arterial pressure, and reduced left ventricular systolic pressure (20 +/- 2 vs. 12 +/- 3 mm Hg, p < 0.

(S)-4'-hydroxypropranolol causes product inhibition and dose-dependent bioavailability of propranolol enantiomers in the isolated perfused rat liver and in rat liver microsomes.

1. Previous evidence suggests that the dose-dependent bioavailability of racemic propranolol may be partly due to product inhibition. We have examined this further by studying the individual enantiomers of propranolol in the perfused rat liver (IPRL) and in rat liver microsomes.

Conjugation of para-nitrophenol by isolated perfused fetal sheep liver.

Using our recently described, isolated perfused fetal sheep liver model, we have studied the metabolism and disposition of para-nitrophenol (PNP) in intact fetal liver. Fetal sheep (mean gestational age, 137 +/- 7 days; range, 127-145 days; n = 8) were delivered under anesthesia near term, and the livers were isolated and perfused in situ, via the umbilical vein, in an oxygenated 1-liter recirculating system, at pH 7.40 at 37 degrees C.

Effect of erythrocyte binding on elimination of harmol by the isolated perfused rat liver.

The effect on the hepatic elimination rate of drug bound to erythrocytes and to albumin was compared with harmol, a relatively hydrophilic drug of high hepatic intrinsic clearance, in the single-pass isolated perfused rat liver preparation (n = 12). The steady-state hepatic extraction ratio (E) of harmol (50 microM) was measured during three consecutive 35-min periods with three different perfusates: Krebs-Henseleit buffer, buffer containing bovine serum albumin (2%), and buffer containing washed human erythrocytes (10%) perfused at 5 mL/min/g liver in randomized order. The mean unbound fraction (fu) of harmol in the latter two perfusates was 0.