Biochemical and molecular pharmacological aspects of transporters as determinants of drug disposition

Membrane transporters are integral membrane proteins typically having 12 transmembrane domains. Most of the SLC family transporters consist of 300-800 amino acid residues with a molecular mass of 40-90 kDa, while the corresponding values of ABC family transporters are 1,200-1,500 residues and 140-180 kDa, respectively. Each transporter has a characteristic tissue distribution and subcellular localization. I have isolated cDNAs of various transporters, including oligopeptide transporter PEPT1, monocarboxylic acid transporter MCT1 and organic cation/carnitine transporters (OCTNs), and determined their tissue distribution and subcellular localization. I have also determined the absolute expression levels of transporters to evaluate their relative contributions to drug transport in various tissues. It is important to note that expression levels of transporters can be changed under various physiological conditions and by administration of drugs. Changes in expression level, subcellular localization and functional properties can all be involved in inter-individual differences in drug pharmacokinetics. Transporters are among the key determinants of drug disposition.     

Six cases of rhabdomyolysis induced by dehydration

Rhabdomyolysis results from a variety of causes. We experienced 6 cases of rhabdomyolysis induced by dehydration in psychoneurosis patients or seniors. We should know dehydration as a risk factor for rhabdomyolysis especially in psychoneurosis patients or seniors.     

Annual Periodic Increases in Serum Carcinoembryonic Antigen Concurrent with Ground-Glass Opacity in the Lung: Report of a Case

A 63-year-old woman underwent a video-assisted thoracoscopic lobectomy for cancer of the right lung in 1999. The following year, a lesion with ground-glass opacity was found in the left lung, and pathological examination after a partial lung resection revealed atypical adenomatous hyperplasia with expression of carcinoembryonic antigen (CEA). During postoperative screening tests for tumor recurrence, there were periodic increases in the serum CEA level by twofold above the normal levels in 2002 and 2003. Clinical evaluations, including laboratory tests, radiographic imaging, and endoscopy examinations, showed no evidence of a CEA-producing tumor, except for a new ground-glass opacity in the left lung. To our knowledge, this is the first report of periodic increases in serum CEA levels in a patient with ground-glass opacity in the lung, not reflecting recurrence of the lung tumor.     

Histopathological studies on the toxicity of ochratoxin A in rats. I. Acute oral toxicity

The acute oral toxicity of ochratoxin A was studied in adult male Wistar rats using single or multiple doses. The oral LD50 was estimated to be 28 mg/kg. The most striking pathologic changes following treatment occurred in the duodenum and jejunum, characterized by severe catarrhal or erosive enteritis which appeared within 4 hr after dosing and subsided within 24 hr. Although near-lethal single doses did not elicit any evidence of renal damage, after several consecutive daily doses, massive acidophilic degeneration with necrosis and desquamation of epithelium occurred in the proximal tubules. Necrosis of cells in germinal centers of the spleen and lymph nodes occurred, indicating a sensitivity of lymphatic tissues to the toxin. Hepatotoxicity was minimal, limited principally to depletion of hepatic glycogen.     

Positioning of retinotopic areas and patterning of cerebral cortex layout

We examined the positioning of human retinotopic areas, which were considered to be homologous with the macaque visual cortices, by applying computational geometry to MRI and fMRI data sets. We found a similarity between the positional relationship of the retinotopic areas in the human and macaque visual cortex, despite the large difference in brain size. This suggests that area maps in different species may share topological features, probably resulting from broad similarities in the patterning mechanism of cerebral cortex layout.     

Evaluation of lumbar tap test combined with mean cerebral blood flow measurement and electroencephalographic topography on idiopathic normal pressure hydrocephalus patients

PURPOSE: To improve the diagnostic precision of the lumbar tap test (LTT). SUBJECTS AND METHODS: Thirty one patients (mean age, 65.4 years; male to female ratio, 12:19) suspected of having idiopathic normal pressure hydrocephalus (INPH) were used in the study. They underwent LTT (20-30 ml of cerebrospinal fluid was drained through a puncture with a 18 G needle; evaluation within 3 days after LTT). Based on changes in symptoms after LTT, including dementia (evaluated according to the duration of time needed to accomplish No. 7 items in the N method psychofunction test) and gait disturbance (evaluated according to the duration and the number of steps needed to walk 4 m in a straight line), mean cerebral blood flow (mCBF) monitored with 133Xe-CT, and electroencephalographic topography (EEG-T). The patients were divided into symptom-improved [LTT (+)] and no change [LTT(-)] groups. Changing patterns of EEG-T and mCBF after LTT and the efficacy of V-P shunt at 1 month after shunt administration (effective: E; non-effective: NE) were analyzed and compared. Changing patterns of EEG-T and mCBF after LTT were categorized as improvement of both parameters (type A), that of mCBF only (type B), that of EEG-T only (type C), and no change in either parameter (type D). RESULTS: (1) Twenty patients were classified as LTT(+) and eleven as LTT(-). (2) The false positive rate was 25% (5/20) for LTT(+); the false negative rate was 27.3% (3/11) for LTT (-). (3) In all the patients, in relation to changing patterns of EEG-T and mCBF, 100% of type A patients (9/9), 75% of type B (6/8), 42.9% of type C (3/7), and 0% of type D (0/7) responded to shunting. (4) Increased rates (IR) of mCBF in 17 patients with improvement of mCBF were 24.2 +/- 10.6% in E patients and 8.9 +/- 5.2% in NE patients, demonstrating a significantly higher percentage in E patients (p < 0.005). The borderline of IR between E and NE was around 15%. CONCLUSION: (1) Although quantitative evaluation of symptoms (dementia and gait disturbance) before and after LTT, 27.3% of false negative and 25% of false positive were recognized. (2) According to changing patterns of EEG-T and mCBF after LTT, all type A patients responded to shunting (E), whereas type D patients were all categorized as NE. (3) When the IR of mCBF was 15% or more after LTT, such patients all responded to shunting. (4) The diagnostic precision of LTT in efficacy evaluation is improved when this test is combined with EEG-T and mCBF, in addition to quantitative evaluation of symptoms.     

Only the light chain is sufficient for the serine protease function of the membrane bound form of factor I on a xeno-surface

The cell membrane-bound forms of whole factor I (fI-PI), the light chain of the serine protease (SP) domain (SP-PI), and the light chain plus the COOH-terminal 45 amino acid (AA) of the heavy chain (SP+45-PI) were constructed. Chinese hamster ovary (CHO) cells, expressing these molecules were established by transfection of cDNA and confirmed by flow cytometry. Amelioration of complement-mediated cell lysis and complement fragment deposition on the cell surface by the transfectant molecules was tested in each CHO cell by means of a lactate dehydrogenase (LDH) assay and flow cytometry, respectively. A highly expressed fI-PI blocked human complement-mediated cell lysis by approximately 84% of the cells. CHO cell transfectants with SP-PI also showed a clear inhibition in cell lysis by human serum, whereas CHO cell transfectants with SP+45-PI showed no inhibition. In addition, fI-PI and SP-PI, but not SP+45-PI, suppressed C5b-9 deposition on CHO cell surface. These data indicate that the last 45 amino acid of the heavy chain, including a disulfide bridge area, did not participate in the serin protease function of factor I. The results suggest that SP-PI has potential for use in clinical xenotransplantation.