ABSTRACT:Rosuvastatin is an HMG-CoA reductase inhibitor and one of the most hydrophilic among the commercially available statins. It is efficiently accumulated in the liver and excreted into the bile in an unchanged form in rats, suggesting that hepatic transporters play a major role in its clearance. Therefore, we investigated the transporters responsible for the hepatic uptake and biliary excretion of rosuvastatin. Uptake studies revealed that human organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 accept rosuvastatin as a substrate. Among the OATP family transporters, OATP1B1 contributes predominantly to the hepatic uptake of rosuvastatin, as estimated with the previously published relative activity factor method, and OATP1B3 is also partly involved. Significant vectorial basal-toapical transport was observed in OATP1B1/multidrug resistanceassociated protein 2 (MRP2), OATP1B1/multidrug resistance protein 1 (MDR1), and OATP1B1/breast cancer resistance protein (BCRP) double transfectants compared with that in an OATP1B1 single transfectant or in vector-transfected control cells. The ATPdependent uptake of rosuvastatin by human BCRP-expressing membrane vesicles was significantly higher than the uptake by green fluorescent protein-expressing control vesicles, suggesting that MRP2, MDR1, and BCRP can transport rosuvastatin. Under in vivo conditions, the biliary excretion clearances based on the intrahepatic concentration of the parent rosuvastatin in Eisai hyperbilirubinemic rats and Bcrp1 knockout mice were reduced to 53% and 12% of those in the control Sprague-Dawley rats and FVB mice, respectively, indicating that rat Mrp2 and mouse Bcrp1 are both partly involved in the biliary excretion of rosuvastatin. These results suggest that multiple transporters are involved in the hepatic uptake and efflux of rosuvastatin.

The recent molecular cloning of the complementary DNA encoding T cell--replacing factor (TRF) has demonstrated that a single molecule is responsible for B cell growth factor II (BCGF-II) activity and eosinophil differentiation activity. It has been proposed that this molecule be called interleukin 5 (IL-5). We previously reported that purified rIL-5 supports the terminal differentiation and proliferation of eosinophilic precursors. In this study, we examined the effects of IL-5 on functional activities of mature eosinophils. IL-5 maintained the viability of mature eosinophils obtained from peritoneal exudate cells of mice infected with parasites. It also induced superoxide anion production in a dose-dependent manner. The Boyden's chamber Millipore assay revealed that IL-5 had a marked chemokinetic effect on eosinophils in a dose-dependent manner. Moreover, IL-5 was found to be an eosinophil chemotactic factor by the checkerboard assay. In conclusion, IL-5 is suggested to play an important role in increasing the functional activities of eosinophils as well as their production in allergic and parasitic diseases.

Reactive oxygen species (ROS) play an important role in the pathogenesis of pulmonary fibrosis. We previously demonstrated that N-acetylcysteine (NAC), an antioxidant, inhibited adhesion molecule expression and cytokine production in lung cells. When NAC is inhaled into the alveolar space, it is expected to directly interact with inflammatory cells and to elevate glutathione levels in the epithelial lining fluids. We therefore examined whether inhaled NAC inhibits lung fibrosis induced by bleomycin (BLM). Male ICR mice were given a single intravenous injection of BLM (150 mg/ kg). Thirty milliliters of NAC (70 mg/ml) or saline were inhaled twice a day for 28 d using an ultrasonic nebulizer. In the inflammatory phase (Day 7), NAC administration attenuated the cellular infiltration in both bronchoalveolar lavage fluid (BALF) and alveolar tissues. At Day 28, the fibrotic changes estimated by Aschroft's criteria and hydroxyproline content in the NAC inhalation group were significantly decreased compared with the BLM-only group (p < 0.05). CXC chemokines, macrophage inflammatory protein-2 (MIP-2), cytokine-induced neutrophil chemoattractant (KC), and CC chemokines, macrophage inflammatory protein-1alpha (MIP-1alpha), in BALF were mostly elevated on Day 7 in the BLM-only group; however, these elevations were significantly repressed by NAC inhalation (p < 0.05). Lipid hydroperoxide (LPO) was also quantified in BALF. LPO was markedly increased on Day 3 in the BLM-only group, and this increase was significantly decreased by NAC inhalation (p < 0.05). These results revealed that aerosolized NAC ameliorated acute pulmonary inflammation induced by BLM injection via the repression of chemokines and LPO production, resulting in the attenuation of subsequent lung fibrosis. These findings are limited to the BLM-induced lung fibrosis animal model. However, NAC inhalation will be expected to be a potential therapy for patients with other interstitial pneumonias because ROS are involved in the pathogenesis of lung injury in most interstitial pneumonia.

ABSTRACT:This study investigated the role of a multispecific organic anion transporter, Oatp1a4/Slco1a4, in drug transport across the blood-brain barrier. In vitro transport studies using human embryonic kidney 293 cells expressing mouse Oatp1a4 identified the following compounds as ]-enkephalin was unchanged. The blood-to-brain transport of digoxin was significantly lower in Oatp1a4(؊/؊) mice than in wild-type mice only when P-gp was inhibited by N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). Taken together, these results show that Oatp1a4 can mediate the brain-to-blood and blood-to-brain transport of its substrate drugs across the blood-brain barrier. The brain-to-plasma ratio of taurocholate, pitavastatin, and rosuvastatin was close to the capillary volume in wild-type mice, and it was not affected by Oatp1a4 dysfunction. Whether Oatp1a4 can deliver drugs from the blood to the brain remains controversial.

Metastasis to the skin from lung cancer is less commonthan metastasis to other organs. We clinically reviewed 16 cases of skin metastasis. The incidence of skin metastasis was 2.8% among all 579 cases of lung cancer. Large cell carcinoma showed the greatest tendency to spread to the skin and epidermoid carcinoma showedthe least tendency. The most commonsites for skin lesions were the back. Almost all lesions ranged from 1 to 5 cm in diameter. Clinical manifestation of skin metastasis was nodular type in all cases. At the development of skin metastasis, all cases were accompaniedby metastasis to other organs. There was only a slight response to combination chemotherapy carried out 5 cases for lung cancer, and most lesions were progressive. Median survival after skin involvement was approximately 4 months. (Internal Medicine 35: 459-462, 1996)