Differential pharmacokinetic drug-drug interaction potential of eletriptan between oral and subcutaneous routes.

1. Pharmacokinetic drug-drug interaction (DDI) data is important from a label claim either in combination drug usage or in polypharmacy situation. 2. Eletriptan undergoes first pass related metabolism through CYP3A4 enzyme to form pharmacologically active N-desmethyl metabolite. 3. Differential DDI interaction of the concomitant oral dosing of ketoconazole (20.1 mg/kg), a CYP3A4 inhibitor, with oral (4.2 mg/kg) or subcutaneous dose (2.1 mg/kg) of eletriptan was evaluated in male Sprague Dawley rats. Serial pharmacokinetic samples were collected and simultaneously analysed for eletriptan/N-desmethyl eletriptan using validated assay. Non-compartmentally derived pharmacokinetic parameters for various treatments were analysed statistically. 4. After oral eletriptan in presence of ketoconazole, Cmax (40 vs. 32 ng/mL alone) and AUCinf (81 vs. 24 ng.h/mL alone) of eletriptan increased; the formation of N-desmethyl eletriptan decreased (Cmax=1.1 ng/mL, 3.9%) with ketoconazole as compared to without treatment (Cmax=3.7 ng/mL, 11.2%). After subcutaneous eletriptan in presence of ketoconazole, there was no change in Cmax (153 vs.152 ng/mL) or AUCinf (267 vs. 266 ng.h/mL) of eletriptan. Formation of N-desmethyl eletriptan after the subcutaneous dose was determined at few intermittent time points with/without ketoconazole. 5. Preclinical data support differential DDI of eletriptan when dosed oral vs. subcutaneous, which need to be evaluated in a clinical setting.

Pharmacokinetic evaluation of differential drug release formulations of rabeprazole in dogs.

Objectives: To develop novel dual release prototype capsule formulations of rabeprazole and evaluation of pharmacokinetic properties relative to the reference product (Aciphex®) in Beagle dogs. Methods: The dual release prototype formulations of rabeprazole were developed by preparing optimized mini-tablets core which was subsequently coated with barrier/enteric coating using standard excipients. Both novel prototype formulations were subjected for in vitro release and assay by HPLC-UV to assess long term stability. Single dose pharmacokinetic study used a single sequence three treatments crossover design. In Periods 1 and 2, four dogs received oral 20 mg dose of two prototype formulations. In Period 3, all dogs received a 20 mg oral dose of Aciphex® reference product. There was a 1-week washout time between two successive periods. A quantitative analysis of rabeprazole/sulfide metabolite in plasma samples was performed using a validated LC-MS/MS assay and PK parameters were estimated by non-compartmental analysis. Results: The stability of the prototype formulations was confirmed over a period of 24 months with an acceptable assay and dissolution data. One of the novel prototype formulations showed 70% oral bioavailability relative to the reference product. Despite a 30% reduced bioavailability, this showed 1 h delay in peak concentration, longer plasma residence time of rabeprazole (up to 12 h) and longer apparent elimination half-life. Conclusions: The use of a canine model has enabled the selection of a novel dual-release prototype formulation of rabeprazole for further clinical development.

An LC-MS/MS assay for the quantitative determination of 2-pyridyl acetic acid, a major metabolite and key surrogate for betahistine, using low-volume human K2 EDTA plasma.

Betahistine is widely used for the treatment of vertigo. Owing to first-pass metabolism, 2-pyridyl acetic acid (2PAA, major metabolite of betahistine) was considered as surrogate for quantitation. A specific and sensitive LC-MS/MS method was developed and validated for quantitation of 2PAA using turbo-ion spray in a positive ion mode. A solid-phase extraction was employed for the extraction of 2PAA and 2PAA d6 (IS) from human plasma. Chromatographic separation of analytes was achieved using an ACE CN, 5 µm (50 × 4.6 mm) column with a gradient mobile phase comprising acetonitrile-methanol (90:10% v/v) and 0.7% v/v formic acid in 0.5 mm ammonium trifluoroacetate in purified water (100% v/v). The retention times of 1.15 and 1.17 min for 2PAA and internal standard, respectively, were achieved. Quantitation of 2PAA and internal standard was achieved by monitoring multiple reaction monitoring transition pairs (m/z 138.1 to m/z 92.0 and m/z 142.1 to m/z 96.1, respectively). The developed method was validated for various parameters. The calibration curves of 2PAA showed linearity from 5.0 to 1500 ng/mL, with a lower limit of quantitation of 5.0 ng/mL. The bias and precision for inter- and intra-batch assays were <10%. The developed method was used to support clinical sample analysis.

Design and synthesis of novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives as thyroid hormone receptor beta (TR-beta) selective ligands.

Design and synthesis of a novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives are reported and their in vitro thyroid hormone receptor selectivity has been evaluated in the thyroid luciferase receptor assay. The 3-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenylamino]-4-hydroxy-cyclobut-3-ene-1,2-dione 21 has shown selectivity towards thyroid hormone receptor beta.

A sensitive assay for ZYAN1 in human whole blood and urine utilizing positive LC-MS/MS electrospray ionization.

AIM: A sensitive LC-MS/MS method was developed and validated for estimation of ZYAN1 in human blood/urine. METHODS: An analog internal standard IOX2 along with ZYAN1 was quantified using selective reaction monitoring in positive mode. The chromatographic separation was performed by gradient elution with C18 analytical column (3 µm, 50 mm × 2.0 mm) with 4-min run time using an acidified mobile phase consisting of ammonium formate and acetonitrile. Protein precipitation enabled extraction of analytes from diluted blood/urine. RESULTS: Calibration curve of ZYAN1 was linear (2-5000 ng/ml). The recovery of ZYAN1 and IOX2 was between 87 and 104%. Interday and intraday accuracy and precision was found well within the acceptance criteria. CONCLUSION: The validated assay was applied for clinical pharmacokinetics of ZYAN1 in healthy volunteers.

Optical fiber humidity sensor based on evanescent-wave scattering.

The phenomenon of evanescent-wave scattering (EWS) is used to design an optical-fiber humidity sensor. Porous solgel silica (PSGS) coated on the surface of a silica optical-fiber core scatters evanescent waves that penetrate the coating layer. Water molecules in the gas phase surrounding the optical fiber can be absorbed into the inner surface of the pores of the porous silica. The absorbed water molecules form a thin layer of liquid water on the inner surface of the porous silica and enhance the EWS. The amount of water absorbed into the PSGS coating is in dynamic equilibrium with the water-vapor pressure in the gas phase. Therefore the humidity in the air can be quantitatively determined with fiber-optic EWS caused by the PSGS coating. The humidity sensor reported here is fast in response, reversible, and has a wide dynamic range. The possible interference caused by EWS to an optical-fiber gas sensor with a reagent-doped PSGS coating as a transducer is also discussed.

A highly sensitive hexachromium monitor using water core optical fiber with UV LED.

A simply structured, cheap hexachromium monitor was developed. The monitor is based on UV/VIS absorption technique. A 2-m long water core optical fiber was employed as a long path length sample cell and a UV light emitting diode (LED) was used as a light source. The emission profile of the UV LED fits very well with the absorption spectrum of chromate ions in water. Therefore, the light-dispersing element, which is usually used in an optical spectrometer, is not necessary in this monitor design. The water core fiber as a long path length makes the monitor highly sensitive for hexachromium detection. This monitor is specific for hexachromium detection without interference from tri-valence chromium ions. A detection limit of 0.1 ng Cr(VI) ml(-1) was obtained with this simple monitor.