The disposition kinetics of six cationic drugs in perfused diseased and normal rat livers were determined by multiple indicator dilution and related to the drug physicochemical properties and liver histopathology. A carbon tetrachloride (CCl 4 )-induced acute hepatocellular injury model had a higher fibrosis index (FI), determined by computer-assisted image analysis, than did an alcohol-induced chronic hepatocellular injury model. The alcohol-treated group had the highest hepatic ␣ 1 -acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (log P app ) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl 4 -treated group and higher in the alcohol-treated group relative to controls. Stepwise regression analysis showed that hepatic extraction ratio, permeabilitysurface area product, tissue-binding constant, intrinsic clearance, partition ratio of influx (k in ) and efflux rate constant (k out ), and k in /k out were related to physicochemical properties of drug (log P app or pK a ) and liver histopathology (FI, MP, or P450). In addition, hepatocyte organelle ion trapping of cationic drugs was evident in all groups. It is concluded that fibrosis-inducing hepatic disease effects on cationic drug disposition in the liver may be predicted from drug properties and liver histopathology.

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Summary. The origin of luminol-dependent chemiluminescence (CL) in neutrophils stimulated by immune complexes (lC) was investigaled. It was found that CL induced by soluble IC and aggregated human gamma globulin (AHG) was glucose-independent, while insoluble IC-induced CL was diminished in the absence of glucose. AHG-induced CL was not inhibited by superoxide dismutase, calalase or 2,5-dimethyl furan, but was suppressed in the presence of phenol, sodium benzoate, sodium formate and mannitol. The CL was also inhibited by inhibitors of arachidonic acid (AA) metabolism including 5,8,11,14-eicosatetraynoic acid, nordihydroguaiaretic acid, quinacrine, indomethacin and aspirin, and by prostaglandins E| and E-j, iheophylMne and dibutyryl cyclic AMP. Luminol-dependent CL was also studied in cell-free systems including AA plus soybean lipoxygenase, hydroperoxyeicosatetraenoic acid plus pcroxidase and xanlhine oxidase plus xanthine. Our results indicate that, in neutrophils exposed to soluble IC and AHG, CL is produced and this is closely linked to the formation of free radicals during the metabolism of AA. The radical(s) involved is likely to include the hydroxyl radical. In neutrophils stimulated by large aggregates of IC or micro-organisms, superoxide anion, HiiO^ and singlet oxygen are also produced as a result of activation of NAD(P)H oxidase. These oxygen species function as oxidizing agents for AA metabolism and amplify the production of hydroxyl radical along the lipoxygenase (and possibly cyclooxygenase) pathway(s).

Four animal models were used to quantitatively evaluate hepatic alterations in this study: (1) a carbon tetrachloride control group (phenobarbital treatment only), (2) a CCl 4 -treated group (phenobarbital with CCl 4 treatment), (3) an alcohol-treated group (liquid diet with alcohol treatment), and (4) a pair-fed alcohol control group (liquid diet only). At the end of induction, single-pass perfused livers were used to conduct multiple indicator dilution (MID) studies. Hepatic spaces (vascular space, extravascular albumin space, extravascular sucrose space, and cellular distribution volume) and water hepatocyte permeability/surface area product were estimated from nonlinear regression of outflow concentration versus time profile data. The hepatic extraction ratio of 3 H-taurocholate was determined by the nonparametric moments method. Livers were then dissected for histopathologic analyses (e.g., fibrosis index, number of fenestrae). In these 4 models, CCl 4 -treated rats were found to have the smallest vascular space, extravascular albumin space, 3 H-taurocholate extraction, and water hepatocyte permeability/surface area product but the largest extravascular sucrose space and cellular distribution volume. In addition, a linear relationship was found to exist between histopathologic analyses (fibrosis index or number of fenestrae) and hepatic spaces. The hepatic extraction ratio of 3 H-taurocholate and water hepatocyte permeability/surface area product also correlated to the severity of fibrosis as defined by the fibrosis index. In conclusion, the multiple indicator dilution data obtained from the in situ perfused rat liver can be directly related to histopathologic analyses. (HEPATOLOGY 2002;36:1180-1189 L iver fibrosis and cirrhosis represent a major worldwide health problem. In cirrhosis, the normal hepatic lobular architecture is replaced by interconnecting bands of fibrous tissue surrounding nodules of regenerating hepatocytes. The sinusoidal stellate cell is central to the fibrotic process. 1-4 Consequently, extravascular space accessible to macromolecules (e.g., albumin) decreases and the distribution of sucrose shows a barrierlimited pattern in the space of Disse instead of the normal flow-limited behavior due to 3 hepatic alterations: (1) collagenization of the space of Disse, (2) formation of a basement membrane of the sinusoid (capillarization), and (3) intrahepatic, portahepatic shunt formation. 5-8 A liver biopsy is currently mandatory to assess severity of fibrosis.We recently examined the drug structure/disposition kinetics of a series of cationic drugs in carbon tetrachloride-and alcohol-induced fibrosis in perfused rat livers. 9 In this case, cationic drug disposition in the fibrotic liver can be predicted from drug properties and liver histopathology. As a result, the question was raised of whether we could use histopathology from patient liver biopsy specimens to estimate changes in hepatic spaces and whether the active and passive transport of probes (e.g., 3 H-taurocholate, 3 H-water) across ...

Polymorphonuclear leukocytes (PMN's) constitute a primary host resistance factor against infection. This study investigated the chemiluminescent (CL) response of peripheral blood PMN's isolated from human subjects with adult periodontitis. 32 subjects were categorized on the basis of age and periodontal disease status into 4 equal groups--young healthy, young diseased, old healthy and old diseased. PMN CL was stimulated using heat-killed, serum-opsonized Fusobacterium nucleatum--a specific periodontopathic gram-negative anaerobe, and Escherichia coli as a gram-negative control organism. The results showed a statistically significant enhancement (p less than 0.05) in the CL response, which was cell associated, in the young diseased subjects. This was not seen in the old subjects (p greater than 0.05), suggesting that in periodontal disease in young subjects the peripheral blood PMNs may be in a metabolically activated state. There was nevertheless a degree of variability between individual subjects within each of the 4 clinical groups.