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The Biopharmaceutics Classification System (BCS) was developed to facilitate estimation of the in vivo pharmacokinetic performance of drugs from human intestinal permeability and solubility. However, the measurement of human in vivo intestinal permeability, unlike that of solubility, is problematic and inefficient. Thus, rat in vitro intestinal permeability results obtained via the Ussing chamber technique are often used instead. However, these data could be unreliable due to difficulty in maintaining the viability of the dissected intestinal membrane in the Ussing chamber. Therefore, a more efficient method to obtain a reliable in vitro permeability is mandatory. Here, we propose a new approach by introducing a novel factor called the permeability ratio (PR). Basically, PR is a rat in vitro intestinal permeability obtained from the Ussing chamber, which is then corrected by the permeability of lucifer yellow, a paracellular permeability marker. To prove the validity of the method, 12 model drugs representing different BCS classes were tested, and the correlation with human in vivo intestinal permeability was high. More importantly, the new method perfectly classified all 12 model drugs. The results indicate that PR is a reliable factor with high correlation to human in vivo intestinal permeability, which can further be used to accurately predict the BCS classification. [ABSTRACT FROM AUTHOR]

1. Identifying kinetic determinants of hepatic elimination of drugs would be crucial for better understanding its pharmacokinetics and predicting drug interactions. Present study investigated the kinetics of sinusoidal uptake of docetaxel and its impact on the overall hepatic elimination of docetaxel in rats. 2. The non-renal clearance (CLNR; hepatic elimination) of docetaxel were significantly reduced by co-administration of intravenous rifampicin, a potent inhibitor of organic anion transporting peptides (OATPs; Oatps), at a dose of 20 mg/kg. Docetaxel uptake into isolated rat hepatocytes was found to be temperature/concentration/energydependent, saturable, and reduced by Oatps inhibitors (rifampicin and bromosulfophthalein). Moreover, docetaxel uptake into perfused rat liver was significantly reduced in the presence of 10-μM rifampicin. However, docetaxel metabolism in rat hepatic microsome was not affected by rifampicin at less than 50 μM. 3. Based on the comparison of intrinsic clearances related to hepatic clearance, it can be suggested that sinusoidal uptake could be the rate-determining process in the overall hepatic elimination of docetaxel in rats. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the usefulness of hematoporphyrin (HP)-modification of the surface of doxorubicin (DOX)-loaded bovine serum albumin (BSA) nanoparticles (NPs) in the liver cancer-selective delivery of DOX. Methods: HP-modified NPs (HP-NPs) were prepared by conjugation of amino groups on the surface of NPs with HP, a ligand for low density lipoprotein (LDL) receptors on the hepatoma cells. In vitro cellular accumulation of DOX, in vivo biodistribution of DOX, safety, and anti-tumor efficacy were evaluated for HP-NPs. Results: Cytotoxicity and accumulation of DOX were in the order of HP-NPs>NPs>solution form (SOL). Cellular uptake from HP-NPs was proportional to the expression level of LDL receptors on the cells, indicating possible involvement of LDL receptor-mediated endocytosis (RME) in uptake. The 'merit index,' an AUC ratio of DOX in liver (target organ) to DOX in heart (major side effect organ) following iv administration of HP-NPs to hepatoma rats, was 132.5 and 4 times greater compared to SOL and NPs, respectively. The greatest suppression of body weight decrease and tumor size increase was observed for iv-administered HP-NPs in tumor-bearing mice. Conclusions: HP modification appears to be useful in selective delivery of NP-loaded DOX to tumors. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of metoprolol after intravenous (IV) (0.5, 1, and 2 mg/kg) and oral (1, 2, and 5 mg/kg) administration, and the intestinal and hepatic first-pass extraction of metoprolol after IV, intraportal, and intraduodenal (1 and 2 mg/kg) administration were comprehensively assessed in rats. Metoprolol exhibited dose-independent pharmacokinetics after IV administration, and dose-dependent pharmacokinetics after oral administration probably due to the saturable first-pass extraction of metoprolol. At doses where metoprolol exhibited dose-independent pharmacokinetics (1 and 2 mg/kg), complete absorption (>99.2%) and low F (<0.245) after oral administration were observed. The intestinal and hepatic first-pass extraction ratio (EG and EH, respectively) of metoprolol were approximately 0.45 and 0.60, respectively (equivalent to approximately 45% and 30% of orally administered dose, respectively), suggesting considerable contribution of intestinal first-pass extraction to the low F of metoprolol in rats. The EG in rats was predicted from in vitro clearance and/or permeability data utilizing the QGut model and well-stirred model (0.347 and 0.626, respectively). The predicted EG values were in good agreement with the observed in vivo EG (0.492–0.443), suggesting the utility of the prediction of in vivo intestinal first-pass extraction from the in vitro clearance using intestinal microsomes. [ABSTRACT FROM AUTHOR]

We previously reported that MDR-1339, an inhibitor of β-amyloid protein aggregation, was likely to be eliminated by biotransformation in rats. The objective of this study was to determine the chemical identity of metabolites derived from this aggregate inhibitor and to characterize the kinetics of formation of these metabolites in rats. Using high performance liquid chromatography coupled with mass spectrometry with a hybrid triple quadrupole-linear ion trap, 7 metabolites and 1 potential metabolic intermediate were identified in RLM incubations containing MDR-1339. In addition to these, 3 glucuronide metabolites were detected in urine samples from rats receiving a 10 mg/kg oral dose of MDR-1339. When the kinetics of the formation of two major metabolites, M1 and M2, were analyzed assuming simple Michaelis-Menten kinetics, the V max and K m values were found to be 0.459 ± 0.0196 nmol/min/mg protein and 28.3 ± 3.07 μM for M1, and 0.101 ± 0.00537 nmol/min/mg protein and 14.7 ± 2.37 μM for M2, respectively. When chemically synthesized M1 and M2 were individually administered to rats intravenously at the dose of 5 mg/kg respectively, the volume of distribution and elimination clearance were determined to be 4590 ± 709 mL/kg and 68.4 ± 5.60 mL/min/kg for M1 and 15300 ± 8110 mL/kg and 98.0 ± 19.5 mL/min/kg for M2, respectively. When MDR-1339 was intravenously administered to rats at a dose of 5 mg/kg, the parent drug and M1 were readily detected for periods of up to 6 h after the administration, but M2 was observed only from 2 to 4 h. A standard moment analysis indicates that the formation clearance of M1 is 6.01 mL/min/kg, suggesting that 19.7% of the MDR-1339 dose was eliminated in rats. These observations indicate that the hepatic biotransformation of MDR-1339 results in the formation of at least 10 metabolites and that M1 is the major metabolite derived from this aggregation inhibitor in rats. [ABSTRACT FROM AUTHOR]

Abstract: The objective of the present study was to develop a rapid and sensitive method for the determination of zabofloxacin, a novel, broad-spectrum fluoroquinolone antibiotic, in rat plasma. Rat plasma samples were deproteinized with methanol, and then were injected into an LC–MS system for quantification. Zabofloxacin and enrofloxacin, which served as an internal standard, were analyzed by selected ion monitoring (SIM) at m/z transitions of 402 for zabofloxacin and 360 for the internal standard. The lower limit of quantification (LLOQ) was determined to be 10ng/mL, with acceptable linearity ranging from 10 to 5000ng/mL (R >0.999). The validation parameters for zabofloxacin, such as absolute matrix effect (107.7–116.0%), accuracy (92.5–101.1% for intra-day and 90.3–103.8% for inter-day), precision (7.7–10.2% for intra-day and 4.2–8.9% for inter-day), and stability in rat plasma (96.0–101.8%), were found to be acceptable according to the assay validation guidelines of the FDA (2001). Following oral administration of zabofloxacin to rats at a dose of 20mg/kg, the concentration of zabofloxacin in plasma was quantifiable in plasma samples collected up to 8h following zabofloxacin administration. The method described in the present study is applicable to routine pharmacokinetic studies in rats. [Copyright &y& Elsevier]

Abstract: Exenatide must be administered serially by twice-daily subcutaneous (SC) injection due to its short half-life. The purpose of the present study is to develop an improved sustained-release exenatide formulation with a therapeutic efficacy comparable to serial, twice-daily injections of exenatide. A novel SR formulation of exenatide, DA-3091, was prepared by single-emulsion solvent evaporation using PLGA. It was administered by SC injection to ZDF rats in single exenatide doses of 0.1, 0.25, 0.5, 1 or 2mg/kg. On the 28th, 49th and 70th days, a 1 or 2mg/kg dose of DA-3091 was further administered to rats in dose groups of 1 or 2mg/kg. The efficacy of DA-3091 was then compared with that of serial, twice-daily SC injections of an exenatide solution for 13 weeks. NFBG and HbA1c concentrations were decreased both significantly and linearly as the exenatide dose in DA-3091 increased. In addition, food intake and body weight were suppressed both significantly and dose-dependently. In equivalent or half doses of exenatide, the efficacy of DA-3091 was comparable to that of twice-daily injections of exenatide solution for 13 weeks. In conclusion, DA-3091 has the potential to be clinically effective when administered every 3 weeks, or less frequently, which promises to significantly improve patient compliance. [Copyright &y& Elsevier]

Abstract: CKD-501 (i.e., lobeglitazone), a potent agonist for both PPARα/γ, is a new drug that has potential clinical applications in the management of type-2 diabetes. The objective of this study was to develop a rapid and sensitive method for the determination of CKD-501 in rat plasma and to assess the applicability of the assay to pharmacokinetic studies. Rat plasma samples were processed using a fast flow protein precipitation (FF-PPT) method and then introduced onto an LC–MS/MS system for quantification. The analyte and rosiglitazone, an internal standard, were analyzed by multiple reactions monitoring (MRM) at m/z transitions of 482.0→258.0 for CKD-501 and 358.0→135.0 for the internal standard. The lower limit of quantification (LLOQ) was determined at 50ng/mL, with an acceptable linearity in the range from 50 to 10,000ng/mL (R >0.999). Validation parameters such as accuracy, precision, dilution, recovery, matrix effect and stability were found to be within the acceptance criteria of the assay validation guidelines, indicating that the assay is applicable to estimating the concentration in the range studied. The concentration of CKD-501 was readily quantifiable in plasma samples up to 24h post-dose in rats that had received an oral dose of 1mg/kg. These observations suggest, therefore, that the validated assay can be used in pharmacokinetic studies of CKD-501 in small animals such as the rat. [Copyright &y& Elsevier]

Abstract: A microemulsion system of docetaxel was prepared and evaluated for its solubilization capacity and oral bioavailability improvement. Based on a solubility study and pseudo ternary phase diagrams, microemulsions of about 30 nm in mean diameter were formulated with improved solubilization capacity towards the hydrophobic drug, docetaxel. The o/w microemulsion formulation (M-3) composed of Capryol 90 (oil), Cremophor EL (surfactant) and Transcutol (co-surfactant) enhanced the solubility of docetaxel up to 30 mg/mL, which maintained solubilization capacity for 24 h even after it was diluted 20 times with normal saline. The three formulations did not show significant difference in the in vitro lipid digestion study. Both the ultrafiltration and dialysis studies revealed that the release of 80% of docetaxel was released from the microemulsions within 12 h in vitro. Compared to the commercial product Taxotere® (0.025 µg/cm2), the apical to basolateral transport of docetaxel across the Caco-2 cell monolayer from the M-3 formulation (Capryol 90/Cremophor EL/Transcutol=29.4:24.9:12.4, w/w) was significantly improved (0.624 µg/cm2, p <0.01). Moreover, the oral bioavailability of the M-3 formulation in rats (34.42%) rose dramatically compared to that of the orally administered Taxotere® (6.63%). This increase in bioavailability was probably due to the combined effect of the enhancement in solubility, the inhibition of P-gp efflux system and the increase in permeability. These results encourage further development of docetaxel microemulsions as an oral drug delivery system. [Copyright &y& Elsevier]

Abstract: Aim of study: The purpose of the present study was to examine the effects of daily administration of an aqueous extract of the dried, immature fruit of Poncirus trifoliata Raf. (Rutaceae) (PF-W) on body weight in rats. Materials and methods: PF-W was used in following experiments: 10-week-long measurement of body weight and food intake, in vitro pancreatic lipase activity assay, in vivo triglyceride concentration study, and measurement of intestinal transit rate. Results: A high dose of PF-W (200mg/2mL/animal/day, in aqueous solution) was administered intragastrically to rats for 10 weeks. PF-W suppressed body weight gain by 6%. However, administration of PF-W at a lower dose (20mg/animal/day) did not reduce weight gain. Administration of low- or high-dose PF-W had no effect on food intake throughout the experimental period. Additional experiments revealed that the suppressive effect of PF-W on body weight gain was not related to pancreatic lipase activity. Moreover, co-administration of PF-W with a lipid emulsion did not reduce plasma triglyceride concentration. Of interest, the high dose of PF-W significantly increased the rate of intestinal transit, whereas oral administration of the lower dose did not. Control and PF-W-treated groups did not differ in hematological and serum biochemical parameters, or in relative organ weights after 10 weeks of high-dose PF-W administration. Conclusion: PF-W does not suppress body weight gain by interfering with fat absorption in a pancreatic lipase-dependent manner. The suppressive effect of PF-W on weight gain is likely due to the increased rate of intestinal transit, and the consequent reduction in nutrient absorption. Moreover, it appears that PF-W is relatively safe for long-term use. Taken together, the results of the present study suggest that long-term, daily administration of PF-W successfully suppressed body weight gain—apparently due to accelerated intestinal transit and not to interference with pancreatic lipase activity. Due to its apparent long-term safety, PF-W is a potential therapeutic agent for reduction of body weight in humans. [Copyright &y& Elsevier]

Although acute renal failure (ARF) has been an area of extensive research in recent decades, our understanding of ARF is far from complete. Organic cations (OCs) are primarily excreted via vectorial transport by various renal organic cation transporters (OCTs). It is reasonable to assume that ARF may alter the expression profiles of these transporters. In a rat ARF model, induction of ARF by uranyl nitrate (UN) treatment significantly decreased the levels of Oct2 (slc22a2) mRNA and protein in the kidney medulla. mRNA expression of the other OCTs was not appreciably altered. The plasma level of testosterone, a well-known regulator of Oct2, was not changed, suggesting that the Oct2 down-regulation is testosterone-independent. The effect of reduced Oct2 expression on the distribution of a model OC, tetraethylammonium (TEA), in various rat tissues including kidney cortex and kidney medulla was investigated during steady state plasma TEA concentrations. The steady state tissue-to-plasma (T/P) TEA ratio was decreased in the kidney medulla (approximately 15-fold) during ARF. These results indicate that, in a rat model of ARF, reduced Oct2 expression in the kidney medulla results in decreased distribution of TEA to the kidney medulla, thereby reducing renal clearance of TEA in UN-ARF rats. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:739–747, 2009 [ABSTRACT FROM AUTHOR]