We examined the relationship between intrapulmonary particle distribution of carbonaceous and mineral dusts and remodeling of the airways along anatomically distinct airway paths in the lungs of Hispanic males from the central valley of California. Lung autopsy specimens from the Fresno County Coroner's Office were prepared by intratracheal instillation of 2% glutaraldehyde at 30 cm H(2)O pressure. Two distinct airway paths into the apico-posterior and apico-anterior portions of the left upper lung lobe were followed. Tissue samples for histologic analysis were generally taken from the intrapulmonary second, fourth, sixth, and ninth airway generations. Parenchymal tissues beyond the 12th airway generation of each airway path were also analyzed. There was little evidence of visible particle accumulation in the larger conducting airways (generations 2-6), except in bronchial-associated lymphoid tissues and within peribronchial connective tissue. In contrast, terminal and respiratory bronchioles arising from each pathway revealed varying degrees of wall thickening and remodeling. Walls with marked thickening contained moderate to heavy amounts of carbonaceous and mineral dusts. Wall thickening was associated with increases in collagen and interstitial inflammatory cells, including dust-laden macrophages. These changes were significantly greater in first-generation respiratory bronchioles compared to second- and third-generation respiratory bronchioles. These findings suggest that accumulation of carbonaceous and mineral dust in the lungs is significantly affected by lung anatomy with the greatest retention in centers of lung acini. Furthermore, there is significant remodeling of this transitional zone in humans exposed to ambient particulate matter.

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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.

This study investigated the relative contribution of ion-trapping, microsomal binding, and distribution of unbound drug as determinants in the hepatic retention of basic drugs in the isolated perfused rat liver. The ionophore monensin was used to abolish the vesicular proton gradient and thus allow an estimation of ion-trapping by acidic hepatic vesicles of cationic drugs. In vitro microsomal studies were used to independently estimate microsomal binding and metabolism. Hepatic vesicular ion-trapping, intrinsic elimination clearance, permeability-surface area product, and intracellular binding were derived using a physiologically based pharmacokinetic model. Modeling showed that the ion-trapping was significantly lower after monensin treatment for atenolol and propranolol, but not for antipyrine. However, no changes induced by monensin treatment were observed in intrinsic clearance, permeability, or binding for the three model drugs. Monensin did not affect binding or metabolic activity in vitro for the drugs. The observed ion-trapping was similar to theoretical values estimated using the pHs and fractional volumes of the acidic vesicles and the pK a values of drugs. Lipophilicity and pK a determined hepatic drug retention: a drug with low pK a and low lipophilicity (e.g., antipyrine) distributes as unbound drug, a drug with high pK a and low lipophilicity (e.g., atenolol) by ion-trapping, and a drug with a high pK a and high lipophilicity (e.g., propranolol) is retained by ion-trapping and intracellular binding. In conclusion, monensin inhibits the ion-trapping of high pK a basic drugs, leading to a reduction in hepatic retention but with no effect on hepatic drug extraction.Basic lipophilic compounds are characterized by a high volume of distribution as a result of extensive tissue uptake. The main mechanisms of such a distribution pattern are nonspecific binding to membrane phospholipids (Bickel and Steele, 1974;Francesco and Bickel, 1977;Romer and Bickel, 1979), binding to microsomal protein (Hung et al., 2002), and the sequestration of the compounds into acidic vesicular compartments such as lysosomes or mitochondria (Daniel et al., 1995). A potential consequence of an apparent irreversible sequestration of basic drugs into acidic vesicles is a potentially reduced drug bioavailability (de Duve et al., 1974;Ohkuma and Poole, 1978) or drug interactions (Daniel and Wojcikowski, 1999b;Nebbia et al., 1999). Lysosomal trapping of basic lipophilic drugs has also been demonstrated to be an important determinant of disposition for desipramine and chloroquine and psychotropic compounds such as the piperidine and piperazine-type neuroleptics (Daniel et al., 2001). The lysosomotropic properties of basic drugs are particularly important determining drug disposition and pharmacokinetics in lysosome-rich organs such as lungs, kidneys, or the liver.Specific studies determining the relative contribution of ion-trapping and microsomal binding to the hepatic retention of drugs or relating the relative uptake to the ph...