Quantitative Analyses of Hepatic OATP-Mediated Interactions Between Statins and Inhibitors Using PBPK Modeling With a Parameter Optimization Method.

This study aimed to construct a widely applicable method for quantitative analyses of drug-drug interactions (DDIs) caused by the inhibition of hepatic organic anion transporting polypeptides (OATPs) using physiologically based pharmacokinetic (PBPK) modeling. Models were constructed for pitavastatin, fluvastatin, and pravastatin as substrates and cyclosporin A (CsA) and rifampicin (RIF) as inhibitors, where enterohepatic circulations (EHC) of statins were incorporated. By fitting to clinical data, parameters that described absorption, hepatic elimination, and EHC processes were optimized, and the extent of these DDIs was explained satisfactorily. Similar in vivo inhibition constant (Ki ) values of each inhibitor against OATPs were obtained, regardless of the substrates. Estimated Ki values of CsA were comparable to reported in vitro values with the preincubation of CsA, while those of RIF were smaller than reported in vitro values (coincubation). In conclusion, this study proposes a method to optimize in vivo PBPK parameters in hepatic uptake transporter-mediated DDIs.

Correlation of mandibular impacted tooth and bone morphology determined by cone beam computed topography on a premise of third molar operation.

PURPOSE: To determine the width and morphology of the mandible in the impacted third molar region, and to identify the location of the mandibular canal prior to planning impacted third molar operations. METHODS: Cone beam computed tomography (CBCT) data of 87 mandibular third molars from 62 Japanese patients were analyzed in this study. The width of the lingual cortical bone and apex-canal distance were measured from cross-sectional images in which the cortical bone was thinnest at the lingual side in the third molar region. Images were used for measuring the space (distance between the inner border of the lingual cortical bone and outer surface of the third molar root), apex-canal distance (distance from the root of the third molar tooth to the superior border of the inferior alveolar canal) and the cortical bone (width between the inner and outer borders of the lingual cortical bone). RESULTS: The means of the space, apex-canal distance and lingual cortical width were 0.31, 1.99, and 0.68 mm, respectively. Impacted third molar teeth (types A-C) were observed at the following frequencies: type A (angular) 37 %; type B (horizontal), 42 %; type C (vertical), 21 %. The morphology of the mandible at the third molar region (types D-F) was observed as: type D (round), 49 %; type E (lingual extended), 18 %; and type F (lingual concave), 32 %. CONCLUSIONS: The width and morphology of the mandible with impacted teeth and the location of the mandibular canal at the third molar region could be clearly determined using cross-sectional CBCT images.

Simultaneous determination of GTP cyclohydrolase activity and biopterin content in pheochromocytoma PC12h cells.

A method to measure the GTP cyclohydrolase and biopterin (BP) content at the same time in the sonicate of pheochromocytoma PC12h cells was described. The cells cultured in a 5-cm dish were sonicated with 0.4 to 0.5 ml of 50 mM Tris-HCl, pH 7.8, and a 50 microliters aliquot was used for one assay. After the GTP cyclohydrolase reaction, dihydroneopterin triphosphate, the reaction product, was oxidized and dephosphorylated to form neopterin (NP); and the pterins in the reaction mixture were then analyzed by high-performance liquid chromatography (HPLC). Mainly three peaks of pterins were detected in the eluate from the HPLC column: they were NP, BP, and 2-amino-4-hydroxypteridine (AHP). The amount of NP was a measure of the enzyme activity. On the other hand, a significant part of the biopterin contained in the enzyme sample was converted to AHP during the GTP cyclohydrolase reaction. Therefore, the sum amount of BP plus AHP was a measure of total BP content in the enzyme sample (sonicate of PC12h cells). The method is convenient and useful to study the actions and action mechanisms of various biologically active substances on the BP level of pheochromocytoma cells in culture.