Pharmacokinetics

The simultaneous effects of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying were evaluated with the test compound 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole(NVS-CRF38), a novel corticotropin releasing factor receptor 1 (CRF1) antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pretreatment of rats with 100 mg/kg oral ABT administered 2 hours before a semisolid caloric test meal markedly delayed gastric emptying...

INTRODUCTION: The treatment of type 2 diabetes mellitus (T2DM) continues to pose challenges for clinicians and patients. The dramatic rise in T2DM prevalence, which has paralleled the rise in obesity, has strained the healthcare system and prompted the search for therapies that not only effectively treat hyperglycemia, but are also weight neutral or promote weight loss. In most clinical situations after diagnosis, patients are advised to adopt lifestyle changes and metformin is initiated to help control blood glucose levels...

Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by joint pain, swelling, stiffness, and progressive destruction of the small joints of the hands and feet. Treatment of RA has improved over the past decade. With multiple cytokines well-known now to play a role in the pathogenesis of RA, including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6, many targeted biological treatments against these cytokines have emerged, changing the treatment of this disease. Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody against the IL-6 receptor and has been approved in many countries, including the United States, for the treatment of moderate to severe RA in patients who have not adequately responded to one or more disease-modifying antirheumatic drugs (DMARDs) or cannot tolerate other approved drug classes for RA...

Prophylaxis with regular infusions of factor VIII (FVIII)- or factor IX (FIX)- containing products is the mainstay of modern hemophilia care. However, this therapeutic regimen is inconvenient, requiring repeated intravenous injections from childhood. Approaches meant to prolong the half-life of FVIII and FIX in plasma have been developed in order to improve the feasibility and acceptability of replacement therapy, extending protection from bleeding, reducing infusion frequency and hence the need for venous access devices in young children...

BACKGROUND: Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages. METHODS: Molecules were tested initially against erythrocytic co-cultures of P...

A sensitive, fast and specific method for the quantitation of pinocembrin in human plasma based on high-performance liquid chromatography-tandem mass spectrometry (LC/MS/MS) was developed and validated. Clonazepam was used as the internal standard (IS). After solid-phase extraction of 500 μL plasma, pinocembrin and the IS were separated on a Luna C8 column using the mobile phase composed of acetonitrile-0.3 mm ammonium acetate solution (65:35, v/v) at a flow rate of 0.25 mL/min in isocratic mode. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring via an electrospray ionization source in negative mode by AB SCIEX Qtrap 5500...

The monoclonal antibody (mAb), h2E2, is a humanized version of the chimeric human/murine anti-cocaine mAb 2E2. The recombinant h2E2 protein was produced in vitro from a transfected mammalian cell line and retained high affinity (4 nM Kd) and specificity for cocaine over its inactive metabolites benzoylecgonine (BE) and ecgonine methyl ester. In rats, pharmacokinetic studies of h2E2 (120 mg/kg i.v.) showed a long terminal elimination half-life of 9.0 days and a low volume of distribution at steady state (Vdss) of 0...

The objective of the study was to compare pharmacokinetic and pharmacodynamic parameters of gliclazide after administration of immediate (IR) and modified release (MR) tablets. The experiment included rats with both normoglycemia and streptozocin (STZ)-induced hyperglycemia. Several MR formulations were designed and in-vitro drug release profile was assessed by a dissolution test. For the further in-vivo study the most suitable formulation was chosen. For pharmacokinetic analysis concentrations of gliclazide in plasma were determined by a validated high performance liquid chromatography (HPLC) method with UV detection...

Contraceptive patches have become a frequently used contraceptive method. We present a mathematical model that describes the serum concentration profiles of Norelgestromin (NGMN) and Ethinylestradiol (EE) released from the contraceptive patch Ortho Evra(®). We propose a simple one-compartment model based on pharmacokinetics data reported in previous studies. The model assumes a time-dependent release rate and a first order elimination rate for each of the active ingredients contained in the patch. The model was applied to noncompliance scenarios, such as total and partial detachment of the patch or prolonged use without patch replacement...

Tacrolimus, a cornerstone of immunosuppressive therapy in solid organ transplantation, has a narrow therapeutic range with considerable inter-individual and intra-individual pharmacokinetic variability. To date, there is no information on the pharmacokinetics of tacrolimus in Iranian liver transplant recipients. This study was designed to determine pharmacokinetic properties of orally administered tacrolimus in Iranian adult liver transplant recipients. Tacrolimus doses and steady state whole blood trough concentrations as well as patient demographic and clinical data were obtained retrospectively using the 30 included patients' medical records...

BACKGROUND: The "molecular tweezer" CLR01 is a broad-spectrum inhibitor of abnormal protein self-assembly, which acts by binding selectively to Lys residues. CLR01 has been tested in several in vitro and in vivo models of amyloidoses all without signs of toxicity. With the goal of developing CLR01 as a therapeutic drug for Alzheimer's disease and other amyloidoses, here we studied its safety and pharmacokinetics. METHODS: Toxicity studies were performed in 2-m old wild-type mice...

The N-ethoxycarbonylmorpholine moiety was evaluated as a novel prodrug moiety for carboxylic acid containing drugs represented by diclofenac (1). Compound 2, the N-ethoxycarbonylmorpholine ester of diclofenac was synthesized and evaluated as a potential prodrug. The stability of the synthesized prodrug was evaluated in solutions of pH 1 and 7.4, and in plasma. The ester's half lives were found to be 8 h, 47 h and 21 min in pH 1, pH 7.4 and plasma, respectively. Equimolar doses of diclofenac sodium and its synthesized prodrug were administered orally to a group of rabbits in a crossover study to evaluate their pharmacokinetic parameters...

Metabolism by cytochrome P4503A (CYP3A) is the most prevalent clearance pathway for drugs. Designation of metabolism by CYP3A commonly refers to the potential contribution by one or both of two enzymes, CYP3A4 and CYP3A5. The metabolic turnover of 32 drugs known to be largely metabolized by CYP3A was examined in human liver microsomes (HLMs) from CYP3A5 expressers (*1/*1 genotype) and nonexpressers (*3/*3 genotype) in the presence and absence of ketoconazole and CYP3cide (a selective CYP3A4 inactivator) to calculate the contribution of CYP3A5 to metabolism...

Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health...

Carmustine (BCNU) implants (Gliadel(®) Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61...

Significant inter-individual variability of exposure for CYP2C19 substrates may be only partly due to genetic polymorphism. Therefore, the in vivo inter-individual variability in hepatic intrinsic clearance (CL(int,h)) of CYP2C19 substrates was estimated from reported AUC values using Monte Carlo simulations. The coefficient of variation (CV) for CL(int,h) in poor metabolizers (PM) expected from genotypes CYP2C19*2/*2, CYP2C19*3/*3 or CYP2C19*2/*3 was estimated as 25.8% from the CV for AUC of omeprazole in PMs...

Detailed analysis of data from studies of recombinant antihemophilic factor produced using a plasma/albumin-free method (rAHF-PFM) in previously treated patients showed a substantial level of interpatient variation in pharmacokinetics (PKs), factor VIII dosing, and annualized bleed rate (ABR), suggesting that individual patient characteristics contributed to outcome. For example, plasma half-life (t1/2), recovery, and clearance appeared to differ between patients aged <6 years and 10-65 years. Prophylaxis resulted in lower ABRs than episodic treatment in both age groups; better adherence to the prophylactic regimen resulted in a lower ABR in patients aged 10-65 years...

A simple, rapid and sensitive chiral capillary zone electrophoresis coupled with acetonitrile-field-amplified sample stacking method was developed that allows the simultaneous enantioselective separation of the mirtazapine, N-demethylmirtazapine, 8-hydroxymirtazapine and mirtazapine-N-oxide. The separation was achieved on an uncoated 40.2 cm×75 μM fused silica capillary with an applied voltage of 16 kV. The electrophoretic analyses were carried out in 6.25 mM borate-25 mM phosphate solution at pH 2.8 containing 5...

Dabrafenib is a potent ATP-competitive inhibitor for the V600 mutant b-rapidly accelerated fibrosarcoma (b-raf) kinase currently approved in the United States for the treatment of metastatic melanoma. Studies were conducted in human liver microsomes, recombinant human cytochrome P450 (P450) enzymes, and human hepatocytes to investigate the potential of dabrafenib and its major circulating metabolites to perpetrate pharmacokinetic drug-drug interactions (DDIs) as well as have their own pharmacokinetics affected (victim) by coadministered drugs...

The aim of this study was to obtain pharmacokinetic data for the anxiolytic compound galphimine-A (G-A) from Galphimia glauca. G-A is the most abundant anxiolytic compound in this plant, while Galphimine-E (G-E) is the most abundant galphimine, but inactive. G-E was transformed chemically into G-A. The pharmacokinetic study was carried out in ICR mice, which were orally administered a single 200 mg/kg dose of G-A. Samples of blood and brain were taken at different times after administration of G-A. Previously, we established the validation of methods for determining the concentration of G-A...