Phenazopyridine-phthalimide nano-cocrystal: Release rate and oral bioavailability enhancement.

Both cocrystal and nanocrystal technologies have been widely used in the pharmaceutical development for poorly soluble drugs. However, the synergistic effects due to the integration of these two technologies have not been well investigated. The aim of this study is to develop a nano-sized cocrystal of phenazopyridine (PAP) with phthalimide (PI) to enhance the release rate and oral bioavailability of PAP. A PAP-PI nano-cocrystal with particle diameter of 21.4±0.1nm was successfully prepared via a sonochemical approach and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and dynamic light scattering (DLS) analysis. An in vitro release study revealed a significant release rate enhancement for PAP-PI nano-cocrystal as compared to PAP-PI cocrystal and PAP hydrochloride salt. Further, a comparative oral bioavailability study in rats indicated significant improvement in Cmax and oral bioavailability (AUC0-∞) by 1.39- and 2.44-fold, respectively. This study demonstrated that this novel nano-cocrystal technology can be a new promising option to improve release rate and absorption of poorly soluble compounds in the pharmaceutical industry.

Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies.

Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer's disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer's disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick's disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies.

Comparison of Times to Ureteral Efflux after Administration of Sodium Fluorescein and Phenazopyridine.

PURPOSE: There is currently a national shortage of indigo carmine. In efforts to identify the most efficient aid for visualizing ureteral efflux intraoperatively we investigated the time to excretion of phenazopyridine vs a newly identified alternative, sodium fluorescein. MATERIALS AND METHODS: We analyzed prospectively collected data on a cohort of women who underwent pelvic reconstructive surgery in 2015. Per provider preference patterns a number of patients were administered 200 mg phenazopyridine orally with a sip of water 1 hour prior to the start of operative time. Other patients were given 0.5 ml 10% sodium fluorescein intravenously in the operating room. In all cases time was measured between the administration of the agent and the visualization of color changes consistent with agent efflux in an indwelling catheter, which was placed at the start of the operation. Differences in excretion times between the groups were compared with the Wilcoxon rank sum test. RESULTS: Seven women received phenazopyridine and 5 received sodium fluorescein. Mean excretion time was significantly longer in the phenazopyridine group compared to the sodium fluorescein group (81.9 vs 5.1 minutes, p = 0.0057). Median excretion time for phenazopyridine was 70 minutes (range 59 to 127) and for sodium fluorescein it was 5 minutes (range 3 to 9). CONCLUSIONS: Sodium fluorescein is excreted significantly faster in the operating room compared to phenazopyridine. Depending on the cost of these agents at an institution, in addition to the desire to decrease operative time, this may impact practice patterns and agent selection.

Determination of phenazopyridine in human plasma by GC-MS and its pharmacokinetics.

A sensitive, selective, and simple gas chromatography-mass spectrometry method is developed for quantitation of phenazopyridine (PAP) in human plasma using internal standard (diazepam). PAP and IS are extracted from plasma by liquid-liquid extraction and analyzed on a DB-5MS column with mass selective detector. Excellent linearity is found between 5-500 ng/mL (r = 0.9992, n = 7) for PAP in human plasma. The limit of detection is 0.3 ng/mL. Intra- and Inter-day precisions expressed as the relative standard deviation for the method are 1.37-6.69% and 1.24-6.01%, respectively. Extraction efficiency is more than 90%, and recoveries are in the range of 92.65-96.21%. This method is successfully applied for the pharmacokinetics and bioequivalence of 2 formulations of PAP in 18 healthy male volunteers who received a single 200 mg dose of each formulation.

Development and validation of a gas chromatography-mass spectrometry method for the determination of phenazopyridine in rat plasma: application to the pharmacokinetic study.

Phenazopyridine hydrochloride is a strong analgesic used in the treatment of urinary tract infections. The aim of the present study was to develop a procedure based on gas chromatography-mass spectrometry (GC-MS) for the analysis of phenazopyridine in rat plasma. The method was set up and adapted for the analysis of small biological samples taken from rats. Biological samples were extracted by liquid-liquid extraction. The extraction agent was ethyl acetate. The samples were separated by GC on a DB-5MS analytical column and determined by a quadrupole mass spectrometer detector operated under selected ion monitoring mode. Excellent linearity was found between 0.01 and 1.00 microg/ml (r = 0.9991, n = 9) for plasma samples. The limit of detection (LOD) was 0.3 ng/ml. Within-day and between-day precisions expressed as the relative standard deviation (RSD) for the method were 1.83-4.91% and 2.12-4.76%, respectively. The recoveries for all samples were >90%. The main pharmacokinetic parameters obtained were T(max) = (0.35+/-0.01) h, C(max) = (0.396+/-0.079) microg/ml, AUC = (0.373+/-0.065) h microg/ml and CL = (94.2+/-5.9) ml/g/h. The results presented here clearly indicate that this proposed method could be applicable to investigate the pharmacokinetic of phenazopyridine in rats after administration. (c)

Ciprofloxacin bioavailability is enhanced by oral co-administration with phenazopyridine: a pharmacokinetic study in a Mexican population.

BACKGROUND: and objective: In Mexico, urinary tract infections (UTIs) constitute the second most frequent type of infections treated at primary-care clinics. Ciprofloxacin has played a major role in the treatment of UTIs because it has a broad spectrum of antibacterial activity. In addition to antimicrobial agents, phenazopyridine has been used to alleviate symptoms that occur during episodes of UTI. Thus, the present study was designed to compare the pharmacokinetic behaviour of ciprofloxacin administered alone versus ciprofloxacin combined with phenazopyridine. PATIENTS AND METHODS: Twenty-four healthy male Mexican volunteers participated in this project. The study was carried out with a single oral dose of ciprofloxacin 500mg. The double-blind, crossover, randomised, balanced trial design comprised two treatments, two periods and two sequences. After administration of the study medication, serial blood samples were collected for a period of 12 hours. The harvested plasma was analysed for ciprofloxacin by high-performance liquid chromatography. The area under the concentration-time curve to last measurable concentration (AUC(t)), area under the concentration-time curve extrapolated to infinity (AUC(infinity)), peak plasma concentration (C(max)), time to reach C(max) (t(max)), mean residence time (MRT), elimination constant (k(e)) and elimination half-life (t(1/2)) were determined from plasma concentrations of both treatments and considered as primary variables for statistical analysis. RESULTS: While there were no differences between the two treatments in terms of C(max) and k(e), AUC(t )and AUC(infinity) were 35% and 29% higher, respectively, in the combined treatment arm. Moreover, a significant delay in t(max )(from 1 to 1.5 hours) and a statistical increase of 29% in MRT were also observed with phenazopyridine co-administration. CONCLUSION: Oral co-administration of phenazopyridine increases ciprofloxacin bioavailability with regard to the amount absorbed (AUC) and permanence in the body (MRT), which could be useful during treatment.

A simple pharmacokinetics subroutine for modeling double peak phenomenon.

Double peak absorption has been described with several orally administered drugs. Numerous reasons have been implicated in causing the double peak. DRUG-KNT--a pharmacokinetic software developed previously for fitting one and two compartment kinetics using the iterative curve stripping method--was modified and a revised subroutine was incorporated to solve double-peak models. This subroutine considers the double peak as two hypothetical doses administered with a time gap. The fitting capability of the presented model was verified using four sets of data showing double peak profiles extracted from the literature (piroxicam, ranitidine, phenazopyridine and talinolol). Visual inspection and statistical diagnostics showed that the present algorithm provided adequate curve fit disregarding the mechanism involved in the emergence of the secondary peaks. Statistical diagnostic parameters (RSS, AIC and R2) generally showed good fitness in the plasma profile prediction by this model. It was concluded that the algorithm presented herein provides adequate predicted curves in cases of the double peak phenomenon.

Determination of phenazopyridine in human plasma via LC-MS and subsequent development of a pharmacokinetic model.

This paper describes a new LC-MS method for the determination of phenazopyridine and the subsequent development of a pharmacokinetic model for phenazopyridine in vivo. Phenazopyridine hydrochloride is a strong analgesic used in the treatment of urinary tract infections. Although it has been used as a clinical treatment for a very long time, pharmacokinetic data and suitable methods for its determination in plasma are currently lacking. The study described in this paper used high performance liquid chromatography-mass spectrometry, HPLC-MS, to determine the plasma concentrations of phenazopyridine in human subjects after oral administration. After liquid-liquid extraction, the phenazopyridine in the plasma was analyzed on a C18 column under SIM mode. A double-peak phenomenon was observed in most of the concentration-time profiles of the subjects. Although some drugs are known to cause this phenomenon, phenazopyridine has not been reported to do so. Several possible causes were analyzed in order to obtain an explanation. We proposed a two-site absorption compartment model to fit the concentration data in vivo, which has one more absorption site than the classical one-compartment model. The model describes the concentration profiles in different dose groups well and could provide an explanation for the double-peak phenomenon. The three dose groups exhibited similar model parameters and a linear pharmacokinetic process over the dose range used.

Metabolism and disposition of phenazopyridine in rat.

1. The blood profile, tissue distribution, biliary and urinary excretion, and metabolism of 14C-phenazopyridine (PAP) was studied in male Wistar rats. 2. Based on the blood profile of 14C the absorption of PAP from the gastrointestinal tract was rapid; the t1/2 of elimination was 7.35 h. 3. Biliary excretion was a major route of elimination with 40.7% dose excreted by this route in bile duct-cannulated rats over the 0-8 h period. The predominant metabolite was conjugated 4'-hydroxy-PAP. 4. Liver and kidney showed the highest tissue levels of PAP-derived 14C, and significant covalent binding was found in these two tissues. 5. The major urinary metabolite of PAP was 4-acetylaminophenol (NAPA) followed in order by 5,4'-dihydroxy-PAP, 5-hydroxy-PAP, 4'-hydroxy-PAP and 2'-hydroxy-PAP; unchanged PAP accounted for < 1% dose. 6. Doubling the dose of PAP to 200 mg/kg caused a proportionate decrease in urinary NAPA excretion and an increase in 5-hydroxy-PAP.