Discovery of Encequidar, First-in-Class Intestine Specific P-glycoprotein Inhibitor.

Many chemotherapeutics, such as paclitaxel, are administered intravenously as they suffer from poor oral bioavailability, partly because of efflux mechanism of P-glycoprotein in the intestinal epithelium. To date, no drug has been approved by the U.S.

Metabolite identification of a new tyrosine kinase inhibitor, HM781-36B, and a pharmacokinetic study by liquid chromatography/tandem mass spectrometry.

Rationale: HM781-36B (1-[4-[4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy]-piperidin-1-yl]prop-2-en-1-one hydrochloride) is a new anticancer drug to treat advanced solid tumors in clinical trial. In order to understand the behavior of HM781-36B in vitro and in vivo we validated an analytical method for HM781-36B and its major metabolites in plasma.

Methods: In vivo and in vitro metabolism of HM781-36B was studied in dog plasma, urine and feces as well as using human and dog liver microsomes with extraction by ethyl acetate or methyl tert-butyl ether, respectively, and successfully separated by high-performance liquid chromatography diode-array detection mass spectrometry (HPLC-DAD/MS).

Antitumor activity of HM781-36B, a pan-HER tyrosine kinase inhibitor, in HER2-amplified breast cancer cells.

HM781-36B is an orally administered pan-human epidermal growth factor receptor (HER) inhibitor. To explore the role of pan-HER inhibitor in breast cancer, we investigated the antitumor effect and mechanisms of HM781-36B in breast cancer cell lines. Six breast cancer cell lines (BT474, MDA-MB-453, SK-BR-3, T47D, MCF-7, and MDA-MB-231) were tested.

Antitumor activity of HM781-36B, an irreversible Pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer.

Trastuzumab, a HER2 directed treatment has shown clinical benefit in HER2 amplified gastric cancer. This study demonstrated the potent antitumor activity of HM781-36B, a quinazoline-based irreversible pan-HER inhibitor, in HER2 amplified gastric cancer cells (SNU216 and N87) in vitro and in vivo. HM781-36B inhibited phosphorylation of HER family and downstream signaling molecules, and induced apoptosis and G1 arrest.

The physicochemical properties, in vitro metabolism and pharmacokinetics of a novel ester prodrug of EXP3174.

EXP3174 is the major active metabolite of losartan, a drug currently widely used for the treatment of cardiovascular diseases. This study was designed to evaluate the physicochemical properties of EXP3174-pivoxil (a novel synthesized prodrug of EXP3174) and characterize its metabolism, regional intestinal absorption and pharmacokinetics by in vitro and in vivo studies. An in vitro metabolism study was conducted in liver and intestinal S9 fractions from different species including rat, dog and human.

Characterization of human liver cytochrome P-450 enzymes involved in the O-demethylation of a new P-glycoprotein inhibitor HM-30181.

HM-30181, 4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide, is a new P-glycoprotein inhibitor with the potential to increase the cytotoxic activity of orally coadministered paclitaxel. This study was performed to characterize human cytochrome P-450 (CYP) enzymes involved in the metabolism of HM-30181 to 4- or 5-O-desmethyl-HM-30181 (M2) and 6- or 7-O-desmethyl-HM-30181 (M3) and to investigate the inhibitory potential of HM-30181 on CYP enzymes in human liver microsomes. CYP3A4 was identified as the major isozyme responsible for the O-demethylation of HM-30181 to M2 and M3 based on the correlation analysis, chemical inhibition and immuno-inhibition study and metabolism in cDNA-expressed human CYP isozymes.

Metabolism of a new P-glycoprotein inhibitor HM-30181 in rats using liquid chromatography/electrospray mass spectrometry.

HM-30181, 4-oxo-4H-chromene-2-carboxylic acid, [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl]amide, is a new P-glycoprotein inhibitor. This study was performed to identify the in vitro and in vivo metabolic pathway of HM-30181 in rats. Rat liver microsomal incubation of HM-30181 in the presence of NADPH resulted in the formation of four metabolites, M1-M4.

Ultrasonic measurement of fetal parameters for estimation of gestational age in Korean black goats.

The objective of this study was to determine relationship of gestational age with measurement of diameter of head, orbit, trunk, long and short axis of heart, aorta, placentome, umbilical cord and umbilical vein in Korean black goats. In this study, ten pregnant Korean black goats (Capra hircus aegagrus) were used. Pregnancy diagnosis was performed with a 5 MHz linear transducer and ultrasonographic scan were performed at 60, 75, 90, 105, 120 and 135 days after mating with a 4-9 MHz convex transducer.

Randomized, open-label, two-period crossover comparison of the pharmacokinetic and pharmacodynamic properties of two amlodipine formulations in healthy adult male Korean subjects.

Background: Amlodipine, a third-generation dihydropyridine calcium antagonist, is prescribed in the management of angina and hypertension. A newly developed amlodipine formulation (amlodipine camsylate) is associated with similar physical properties, melting point, and solubility-and improved stability against long-term stability test and accelerated temperature test-compared with the conventional formulation (amlodipine besylate).

Objective: This study was performed to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of a newly developed amlodipine formulation with a conventional formulation in healthy male subjects.

Novel oral formulation of paclitaxel inhibits neointimal hyperplasia in a rat carotid artery injury model.

Background: Paclitaxel has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal formation. This study tested whether novel oral formulations of paclitaxel can prevent neointimal formation in a rat carotid artery injury model.

Methods And Results: Oral formulations of paclitaxel (0, 5, 7.