Quetiapine (QTP) is an atypical antipsychotic drug commonly used to treat several psychiatric disorders and is metabolized into the active metabolite norquetiapine (NQTP). This study was designed to evaluate and compare the physicochemical properties, metabolic stability, brain distribution, and pharmacokinetics of QTP and NQTP. Compared to QTP, NQTP had a higher pK a , solubility, and rat liver microsomal stability, optimal log D and similar log P values. For pharmacokinetic evaluation, QTP and NQTP were administered orally and intravenously to rats at various doses. The plasma QTP and NQTP concentrations in rats were determined by a fully-validated liquid-chromatography tandem mass spectrometry (LC-MS/MS). Over the investigated dosing range, both QTP and NQTP showed linear pharmacokinetics. Following oral administration of the same dose, the area under the concentration-time curve (AUC 0-∞ ) and maximum serum concentration (C max ) were larger after NQTP administration compared to QTP administration. In addition, NQTP had a greater absolute oral bioavailability compared to QTP (15.6% vs. 0.63%, respectively). The brain-to-plasma concentration ratio was greater after NQTP administration compared to the QTP and NQTP ratios after QTP administration. NQTP administration results in increased systemic exposure and brain distribution compared to QTP administration. Future studies are needed to evaluate the pharmacologic and toxicologic effects of increased NQTP exposures.Key words permeability; pharmacokinetics; quetiapine; norquetiapine; solubility Quetiapine (QTP) is an atypical antipsychotic drug that has been commonly prescribed for treatment of schizophrenia and related psychotic disorders since its introduction in 1996. It belongs to the group of second-generation antipsychotics (SGAs) that were initially developed to have a lesser likelihood of precipitating extrapyramidal symptoms (EPS) and possibly tardive dyskinesia compared to the first generation antipsychotics (FGA).1,2) QTP is also a biopharmaceutics classification system (BCS) class II compound with high permeability and moderate solubility.3) QTP is extensively metabolized by hepatic CYP system, primarily by CYP3A, through sulfoxidation, N-and Odealkylation, and, to a lesser degree, 7-hydroxylation. 4,5) NDesalkyl quetiapine, also known as norquetiapine (NQTP), is an important QTP metabolite produced by CYP3A4. 6)According to a previous study, the pharmacokinetic variability of QTP was substantially greater in psychiatric patients compared to NQTP. 7) Several factors may contribute to the inter-individual pharmacokinetic variability of QTP. Co-administered CYP3A inducers (e.g., carbamazepine, phenytoin) or inhibitors (e.g., ketoconazole, itraconazole, erythromycin, and fluvoxamine) may interact with QTP, resulting in the increased or decreased production of NQTP, respectively. 8,9) Due to the lack of CYP3A4 genetic polymorphisms, genotypes may not be associated with the variability in QTP metabolism.QTP is metabolized into more than 20 metabolites, bu...

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The purposes of the present study were to develop a self-microemulsifying drug delivery system (SMEDDS) containing bortezomib, a proteasome inhibitor. The solubility of the drug was evaluated in 15 pharmaceutical excipients. Combinations of oils, surfactants and cosurfactants were screened by drawing pseudo-ternary phase diagrams. The system exhibiting the largest region of microemulsion was considered optimal. Bortezomib SMEDDS spontaneously formed a microemulsion when diluted with an aqueous medium with a median droplet size of approximately 20-30 nm. In vitro release studies showed that the SMEDDS had higher initial release rates for the drug when compared with the raw drug material alone. Measurement of the viscosity, size, and ion conductivity indicated that a phase inversion from water in an oil system to oil in a water system occurred when the weight ratio of the water exceeded 30% of the entire microemulsion system. In a pharmacokinetics study using rats, the bortezomib microemulsion failed to improve the bioavailability of the drug. The reason was assumed to be degradation of the drug in the microemulsion in the gastrointestinal tract. However, bortezomib in Labrasol ® solution (an aqueous solution containing 0.025% Labrasol ® ) showed significantly increased area under the curve from 0-24 h (AUC 0-24 h ) and maximum plasma concentration (C max ) values compared to the drug suspension. The findings of this study imply that oral delivery of a bortezomib and colloidal system containing Labrasol ® could be an effective strategy for the delivery of bortezomib.Key words bortezomib; labrasol; microemulsion; self-microemulsifying drug delivery system (SMEDDS); pharmacokinetics Bortezomib, marketed as Velcade ® in the United States, is a proteasome inhibitor for the treatment of relapsed multiple myeloma and mantle cell lymphoma. The mechanisms of the drug associated with its anticancer activity are clear that proteasome inhibition could promote degradation of anti-apoptotic proteins and prevent degradation of pro-apoptotic proteins, resulting in programmed cell death in malignant cells. 1)Bortezomib is administered to the patients as intravenous or subcutaneous injections. It was reported that the drug could be orally available in the early stage of development. However, oral delivery of the drug has been not investigated and there has been no pharmacokinetic parameter related to oral absorption.2) It was suspected that oral absorption of bortezomib was limited due to low aqueous solubility of the drug and efflux by P-glycoproteins (P-gp). 3,4)Microemulsion is a colloidal system which consists of oil, water, surfactants and cosurfactants. They can offer the advantages including simple manufacturing processes, thermodynamic stability, nano-sized droplets and improved solubilization of poorly soluble drug.5) Therefore, they could be potentially excellent carriers for the drug with low solubility and have been applied in various administrations such as oral, intranasal and vaginal routes.6-10) Pre-concentrates of...