Plasma Propranolol Research Articles

Physiologically Based Pharmacokinetic Model of Brain Delivery of Plasma Protein Bound Drugs

IntroductionA physiologically based pharmacokinetic (PBPK) model is developed that focuses on the kinetic parameters of drug association and dissociation with albumin, alpha-1 acid glycoprotein (AGP), and brain tissue proteins, as well as drug permeability at the blood–brain barrier, drug metabolism, and brain blood flow.GoalThe model evaluates the extent to which plasma protein-mediated uptake (PMU) of drugs by brain influences the concentration of free drug both within the brain capillary compartment in vivo and the brain compartment. The model also studies the effect of drug binding to brain tissue proteins on the concentration of free drug in brain.MethodsThe steady state and non-steady state PBPK models are comprised of 11–12 variables, and 18–23 parameters, respectively. Two model drugs are analyzed: propranolol, which undergoes modest PMU from the AGP-bound pool, and imipramine, which undergoes a high degree of PMU from both the albumin-bound and AGP-bound pools in plasma.ResultsThe free propranolol concentration in brain is under-estimated 2- to fourfold by in vitro measurements of free plasma propranolol, and the free imipramine concentration in brain is under-estimated by 18- to 31-fold by in vitro measurements of free imipramine in plasma. The free drug concentration in brain in vivo is independent of drug binding to brain tissue proteins.ConclusionsIn vitro measurement of free drug concentration in plasma under-estimates the free drug in brain in vivo if PMU in vivo from either the albumin and/or the AGP pools in plasma takes place at the BBB surface.

Mucoadhesive buccal tablets with propranolol hydrochloride: Formulation development and in vivo performances in experimental essential hypertension

The objective of this study was to formulate extended-release mucoadhesive buccal tablets of propranolol hydrochloride in order to provide a prolonged absorption of propranolol hydrochloride from the buccal mucosa and to reduce presystemic metabolism and thus provide a better therapeutic effect. Besides, the aim was to perform comparative in vivo pharmacokinetic and hemodynamic studies of the developed extended-release (ER) propranolol hydrochloride 10 mg mucoadhesive buccal tablets and commercial immediate-release (IR) propranolol hydrochloride 10 mg tablets in spontaneously hypertensive rats. Formulation with 15% polyethylene oxide showed the highest degree of propranolol hydrochloride permeation, satisfactory mucoadhesiveness, and extended-release of propranolol hydrochloride, thus it was selected for further in vivo study. The pharmacokinetic study in rats showed the superiority of ER mucoadhesive buccal tablets over IR tablets in terms of propranolol hydrochloride absorption extent (AUC values: 70.32 ± 19.56 versus 31.69 ± 6.97 µg·h/mL), although lower maximum plasma propranolol hydrochloride concentration (Cmax) was achieved. However, no statistically significant difference was observed in Cmax between these treatments. The hemodynamic study showed that ER mucoadhesive buccal tablets provide a more pronounced decrease primarily in heart rate, but also in systolic and diastolic arterial pressure, as well as a longer heart rate reduction compared to IR tablets.

Alpha-1 Acid Glycoprotein as a Biomarker for Subclinical Illness and Altered Drug Binding in Rats.

Alpha-1 acid glycoprotein (AGP) is a significant drug binding acute phase protein that is present in rats. AGP levels are known to increase during tissue injury, cancer and infection. Accordingly, when determining effective drug ranges and toxicity limits, consideration of drug binding to AGP is essential. However, AGP levels have not been well established during subclinical infections. The goal of this study was to establish a subclinical infection model in rats using AGP as a biomarker. This information could enhance health surveillance, aid in outlier identification, and provide more informed characterization of drug candidates. An initial study (n = 57) was conducted to evaluate AGP in response to various concentrations of Staphylococcus aureus (S. aureus) in Sprague-Dawley rats with or without implants of catheter material. A model validation study (n = 16) was then conducted using propranolol. Rats received vehicle control or S. aureus and when indicated, received oral propranolol (10 mg/kg). Health assessment and blood collection for measurement of plasma AGP or propranolol were performed over time (days). A dose response study showed that plasma AGP was elevated on day 2 in rats inoculated with S. aureus at 106, 107 or, 108 CFU regardless of implant status. Furthermore, AGP levels remained elevated on day 4 in rats inoculated with 107 or 108 CFUs of S. aureus. In contrast, significant increases in AGP were not detected in rats treated with vehicle or 10³ CFU S. aureus. In the validation study, robust elevations in plasma AGP were detected on days 2 and 4 in S. aureus infected rats with or without propranolol. The AUC levels for propranolol on days 2 and 4 were 493 ± 44 h × ng/mL and 334 ± 54 h × ng/mL, respectively), whereas in noninfected rats that received only propranolol, levels were 38 ± 11 h × ng/mL and 76 ± 16. h × ng/mL, respectively. The high correlation between plasma propranolol and AGP demonstrated a direct impact of AGP on drug pharmacokinetics and pharmacodynamics. The results indicate that AGP is a reliable biomarker in this model of subclinical infection and should be considered for accurate data interpretation.

Propranolol Therapy in Infantile Hemangioma: It Is Not Just About the Beta.

Propranolol, a nonselective β-adrenergic receptor antagonist, is approved by the U.S. Food and Drug Administration to treat problematic infantile hemangiomas, but a subset of patients experience treatment complications. Parents wary of long-term use and side effects consult plastic surgeons on surgical options or as a second opinion. Understanding the mechanism(s) of action of propranolol will allow plastic surgeons to better inform parents. A systemic literature search was performed to query published translational and basic science studies on propranolol effects on infantile hemangiomas and cells derived from these lesions. In experimental studies, propranolol was antiproliferative and cytotoxic against hemangioma endothelial and stem cells and affected infantile hemangioma perivascular cell contractility. Propranolol inhibited migration, network formation, vascular endothelial growth factor A production, and vascular endothelial growth factor receptor 2 activation and down-regulated PI3K/AKT and mitogen-activated protein kinase signaling in hemangioma endothelial cells, but it increased ERK1/2 activity in hemangioma stem cells. At effective clinical doses, measured propranolol plasma concentration is 100 times higher than necessary for complete β-adrenergic receptor blockade, yet was 10 to 100 times less than required to induce hemangioma stem cell death. Propranolol targets multiple cell types in infantile hemangiomas by means of β-adrenergic receptor-dependent and -independent mechanisms. Plasma concentration played a significant role. At clinically relevant doses, incomplete infantile hemangioma suppression may explain the rebound phenomenon and worsening ulceration, and propranolol off target effects may lead to commonly reported adverse effects, such as sleep and gastrointestinal disturbances. Propranolol limitations and complications underscore the importance of surgical treatment options in cases of rebound and severe adverse effects. Surgical intervention remains an important treatment choice when parents are hesitant to use propranolol.

Simultaneous extraction and preconcentration of three beta (β)-blockers in biological samples with an efficient magnetic dispersive micro-solid phase extraction procedure employing in situ sorbent modification

A straightforward and sensitive magnetic dispersive micro-solid phase extraction based on in situ sorbent modification in sample solution was developed for the simultaneous extraction of metoprolol, atenolol, and propranolol (three beta-blockers) in human plasma and urine samples. To prepare a suitable sorbent, magnetic graphene oxide as a magnetic core was synthesized and modified with sodium dodecyl sulfate in the sample solution containing the analytes. In the procedure, the sorbent synthesis and the analyte extraction were simultaneously performed in the sample solution, which leads to a reduction in the time and cost of the determination of the analytes. Three surfactants such as cetyltrimethylammonium bromide, triton X100, and sodium dodecyl sulfate were utilized to modify the magnetic graphene oxide composites and their effects on the extraction of beta-blockers were investigated. The effective variables in the microextraction process of the analytes were optimized based on a design of experiment strategy. Under the optimal conditions, the dynamic ranges of linear were 5–10000, 50–5000, and 10–5000 ng mL–1 with method detection limits of 0.8, 10, and 2 ng mL– 1 for Atenolol, Metoprolol, and Propranolol, respectively The relative standard deviations of the intra-day and inter-day were less than 2.96% and 5.35% (n = 5) for the determination of the analytes, respectively. A suitable enrichment factors of 14, 16, and 18 were obtained for the determination of metoprolol, atenolol, and propranolol, respectively. Finally, the suggested method was successfully applied to measure the beta-blockers in several plasma and urine samples of healthy volunteers without taking drugs and patient volunteers with taking drugs. The method shows suitable relative recoveries in the ranges of 82.4–109.4% and 77.6–95.9% for the analysis of urine and plasma samples with relative standard deviations between 3.1 and 6.7% for the determination of all analytes, respectively.

Systematic development of a bioanalytical UPLC-MS/MS method for estimation of risperidone and its active metabolite in long-acting microsphere formulation in rat plasma

A systematic approach to develop a UPLC-MS/MS method was applied for quantifying of risperidone (RISP), its active metabolite, 9-hydroxy risperidone (9-OH-RISP) and internal standard (propranolol) in rat plasma. Liquid-liquid extraction was performed using methyl tert-butyl ether for quantification of drug and its active metabolite by MS detection in the positive ion mode. Acquity UPLC system with BEH C18 (2.1 mm × 100 mm, particle size 1.7 μm) column was used along with acetonitrile (0.1% formic acid)–2 mM (milli mole) ammonium acetate in isocratic condition was used as the mobile phase. Detection was performed by multiple reactions monitoring with precursor-to-product ion transitions with m/z 411.2 → 191.0 for RISP, m/z 427.2 → 207.0 for 9-OH-RISP and m/z 260.1 → 116.0 for IS. The method was validated as per the FDA guidance on bioanalytical method validation. Linearity (r2 = 0.999) was observed in the drug concentration ranging between 0.1 and 50 ng mL−1, while all other parameters were found to be within the acceptable ranges. Method robustness was optimized by Box-Behnken design to monitor the influential variables to achieve maximal recovery of the analytes in the rat plasma. Pharmacokinetic evaluation of the analytes from long-acting microparticles in rat plasma showed two peaks indicating an initial burst effect within 24 h of administration followed by controlled drug release pattern upto 45 days, while marketed formulation (Risperdal Consta®) showed no plasma concentration during the lag-time of 21 days followed by maximal drug absorption between 28 and 40 days.

Intermittent β-adrenergic blockade downregulates the gene expression of β-myosin heavy chain in the mouse heart

Expression of the β-myosin heavy chain (β-MHC), a major component of the cardiac contractile apparatus, is tightly regulated as even modest increases can be detrimental to heart under stress. In healthy hearts, continuous inhibition of β-adrenergic tone upregulates β-MHC expression. However, it is unknown whether the duration of the β-adrenergic inhibition and β-MHC expression are related. Here, we evaluated the effects of intermittent β-blockade on cardiac β-MHC expression. To this end, the β-blocker propranolol, at the dose of 15mg/kg, was administered once a day in mice for 14 days. This dosing schedule caused daily drug-free periods of at least 6 h as evidenced by propranolol plasma concentrations and cardiac β-adrenergic responsiveness. Under these conditions, β-MHC expression decreased by about 75% compared to controls. This effect was abolished in mice lacking β1- but not β2-adrenergic receptors (β-AR) indicating that β-MHC expression is regulated in a β1-AR-dependent manner. In β1-AR knockout mice, the baseline β-MHC expression was fourfold higher than in wild-type mice. Also, we evaluated the impact of intermittent β-blockade on β-MHC expression in mice with systolic dysfunction, in which an increased β-MHC expression occurs. At 3 weeks after myocardial infarction, mice showed systolic dysfunction and upregulation of β-MHC expression. Intermittent β-blockade decreased β-MHC expression while attenuating cardiac dysfunction. In vitro studies showed that propranolol does not affect β-MHC expression on its own but antagonizes catecholamine effects on β-MHC expression. In conclusion, a direct relationship occurs between the duration of the β-adrenergic inhibition and β-MHC expression through the β1-AR.

Applications of shun shell column and nanocomposite sorbent for analysis of eleven anti-hypertensive in human plasma

High-performance liquid chromatography (HPLC) and solid phase micro membrane tip extraction (SPMMTE) methods are developed for the simultaneous analysis of eleven cardiovascular drugs in human plasma. Iron nanoparticles were obtained by the green method, characterized by XRD, FT-IR, TEM, and EDS and utilized in SPMMTE for sample preparation. The mobile phase used was ammonium acetate buffer-methanol–acetonitrile (65:18:17) with a 1.0 mL/min flow rate at 260 nm detection. Column used was Sunshell C18 150 × 4.6 mm, 2.6 µm. The values of k, α, and Rs were ranged from 040 to109.22, 1.20 to 2.67 and 1.0 to 26.18. SPMMTE and HPLC methods were fast, reproducible, precise, robust, economic and rugged for analysis of methyldopa, hydrochlorothiazide, prazosin hydrochloride, furosemide, labetalol, propranolol, valsartan, losartan potassium, diltiazem, irbesartan and spironolactone in human plasma. The recoveries (%) of methyldopa, hydrochlorothiazide, prazosin hydrochloride, furosemide, labetalol, propranolol, valsartan, losartan potassium, diltiazem, irbesartan, and spironolactone were 91.0, 85.2, 92.3, 90.4, 90.1, 85.6, 86.6, 86.2, 85.1, 86.6, and 85.7, respectively. These results showed that SPMMTE and HPLC methods can be applied to test the described drugs in several matrices.

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective.Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial.Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297– 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment.Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a β-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results.Clinical Trial Registration The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Pharmacokinetic Drug-Drug Interaction and Responsible Mechanism between Memantine and Cimetidine.

A sensitive and simple chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to evaluate memantine in rat plasma. Memantine and propranolol (internal standard) in rat plasma was extracted using a methanol precipitation method. The standard curve value was 0.2–1000 ng/mL and selectivity, linearity, inter-day and intra-day accuracy and precision were within acceptance criteria. Using this validated method, drug-drug interactions between memantine and cimetidine was measured following co-administration of memantine and cimetidine intravenously and orally. Plasma exposure of memantine was increased by 1.6- and 3.0-fold by co-medication with cimetidine intravenously and orally, respectively. It suggested that the drug interaction occurred during the gut absorption process, which was consistent with the results showing that the intestinal permeability of memantine in the presence of cimetidine was 3.2-fold greater than that of memantine alone. Inhibition of cimetidine on hepatic elimination of memantine rather than renal excretion was also attributed to the drug-drug interaction between memantine and cimetidine, which explained the decreased clearance of memantine by co-medication with cimetidine. In conclusion, the newly developed simple and sensitive LC-MS/MS analytical method was applied to investigate the pharmacokinetic drug-drug interactions of memantine. Plasma exposure of memantine by co-administration with cimetidine was increased because of its enhanced intestinal permeability and the decreased metabolic activity of memantine.

Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial

BackgroundRetinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1).MethodsA multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23–32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations.DiscussionPropranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue.Trial registrationClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014–005472-29.

Propranolol kinetics in plasma from severely burned adults

ObjectivesThe aim of this study was to determine the appropriate propranolol dosing strategy for reducing heart rate in severely burned adults. MethodsA total of 26 patients (≥18 years) with burns covering ≥30% of the total body surface area were included in this IRB-approved study. Plasma propranolol concentrations were determined in a placebo group (n=10) or following one of three dosing strategies: Q6 (n=4), Q8 (n=6), and Q24 (n=6). Blood was collected just before dosing and at regular intervals over two dosing periods with corresponding heart rate and blood pressure recordings. Statistical significance was determined by one-way ANOVA followed by the appropriate post-hoc test. ResultsHeart rate was 86±2 bpm for Q6, 93±3 bpm for Q8, and 90±4 bpm for Q24. The Q8 group had a significantly higher heart rate than the Q6 group (p=0.0001). Plasma propranolol concentrations were significantly higher in the Q6 dosing strategy than in the Q8 dosing strategy (p=0.02). ConclusionsHeart rate can be decreased to a similar degree with Q6 and Q24 dosing strategies, with the Q8 dosing strategy being less effective. Q6 dosing is recommended to maintain reduced heart rate throughout dosing periods.

Quantification of alprenolol and propranolol in human plasma using a two-dimensional liquid chromatography (2D-LC)

A new two-dimensional liquid chromatography (2D-LC) method using a column switching valve, with a restricted-access media (RAM) column in the first dimension was developed and validated for the quantification of two β-blockers in human plasma. Several parameters, such as sample collection, mobile phase composition and flow rate for sample cleanup, transference and analytical separation of the β-blockers were investigated and optimized. The developed method allowed for the simultaneous pre-treatment and quantification of alprenolol (ALP) and propranolol (PRO) in human plasma in less than 25min. The method consisted in the injection of 100μL of plasma samples on the RAM alkyl-diol-silica column (Lichrospher® RP-18 ADS, 25μm) with water/acetonitrile (98:2, v/v; at a flow rate of 2.0mL/min) and then transferred (via a six-port valve) to the analytical column (Luna PFP (2), 150×4.6mm ID, 100Å, 3μm) with 0.1% (v/v) triethylamine in water acidified with trifluoroacetic acid (pH=3)/acetonitrile (74:26, v/v) at a flow rate of 0.6mL/min in a back-flush mode. The column oven temperature was optimized to 42°C and the fluorescence detector set at 280nm and 310nm (excitation and emission, respectively). The method was validated according to the European Medicines Agency’s guidelines and was linear (r2>0.999) over a dynamic range of 5.0 – 200ng/mL. Recoveries ranged from 90.2 and 107% and the lower limit of quantification was 5.0ng/mL for both compounds. Precision was expressed as a percentage of relative standard deviation and did not exceed 11%. Finally, the method was successfully applied to determine the plasma concentration of PRO in four healthy volunteers.

Oxandrolone Coadministration Does Not Alter Plasma Propranolol Concentrations in Severely Burned Pediatric Patients.

The systemic impact of severe burn injury results in a variety of disorders that require therapeutic intervention. Propranolol, a nonselective β1, β2-adrenergic receptor antagonist, reduces resting heart rate and cardiac work caused by elevated circulating catecholamines. Oxandrolone, a testosterone mimetic, promotes protein synthesis and anabolism to counter muscle wasting. Coadministration of these drugs is expected to synergistically improve patient outcomes. Testosterone administration is known to alter β-adrenergic receptor-mediated signaling. Here, we determined whether the coadministration of oxandrolone alters plasma propranolol concentrations. Ninety-two pediatric patients with burns covering ≥30% of the TBSA were enrolled in this institutional review board-approved study and randomized to receive propranolol (n = 49) or oxandrolone + propranolol (n = 43). Plasma propranolol concentrations were determined following two dosing strategies: Q6 (liquid formulation; n = 86) and Q24 (extended-release capsule; n = 22). Samples were drawn before drug administration and at regular intervals throughout the next two dosing periods. Heart rate and blood pressure were recorded throughout the study. Propranolol half-life was 3.3 hours for the Q6 drug dosing frequency (P < .0001) and 11.2 hours for the Q24 strategy (P < .0001). Percentage of predicted heart rate declined by 2.8% for each doubling of the propranolol concentration in the Q6 dosing schedule (P < .0001). Percentage of predicted heart rate declined by 2.5% for each doubling of propranolol concentration on the Q24 dosing schedule (P < .0001). Maximum and minimum propranolol plasma concentrations were similar with either dosing regimen. The addition of oxandrolone did not affect any of the measured parameters. Oxandrolone coadministration does not alter propranolol’s plasma concentration, half-life, or effect on heart rate. This study is registered at clincialtrials.gov: NCT00675714.

SPMMTE and HPLC Methods for the Analyses of Cardiovascular Drugs in Human Plasma Using New Generation C28 Column

Background: The examination of cardiovascular drugs is very imperative in human beings. For this, the sample research is very crucial prior to analysis as these drugs are in attendance at low amounts in human plasma. Introduction: Low-cost solid phase micro membrane tip extraction and high performance liquid chromatographic methods were offered for examining propranolol, aspirin and atorvastatin in human plasma. Method: Green production of iron nano composite sorbent was obtained efficiently with 90% product. The surface showed of uneven features of the nano particles. The produced iron nano composite sorbent was used in solid phase micro membrane tip extraction. The examination of propranolol, aspirin and atorvastatin in human plasma was done using solid phase micro membrane tip extraction high performance liquid chromatographic and methods. Results: New generation C28 stationary phase was exploited with phosphate buffer:acetonitrile (30:70, v/v; pH 3.0) as eluent. 1.0 mL/min was marinated as flow of eluent with detection at 236 nm. The extent of retention factor was 1.70, 2.40 and 4.30. The separation and resolution factors extents were 1.41 & 1.81 and 1.40 & 3.80, respectively. The peaks were sharp with base lined resolution. The percentage recoveries of propranolol, aspirin and atorvastatin in standard and plasma samples were 90.5, 90.0 & 37.0 and 17.5, 16.0 & 7.0, respectively. Conclusion: The produced solid phase micro membrane tip extraction high performance liquid chromatographic and methods were reproducible, quick, exact, tough, rough and fiscal for the examination of propranolol, aspirin and atorvastatin in human plasma. Keywords: Nanocomposite adsorbent, propranolol, aspirin, atorvastatin, new generation C28 column, human plasma, SPMMTE.

Periocular Tissue Concentrations of Propranolol after Ocular Instillation of a Gel-Forming Solution.

The aim of this study was to determine the concentrations of propranolol in periocular tissues and plasma after ocular instillation of 0.5% propranolol gel-forming solution (GFS) as compared to 0.5% propranolol non-gelforming solution (non-GFS) for potential use in the treatment of periocular capillary hemangiomas. A GFS prepared in 1% sodium alginate or a non-GFS in phosphatebuffered saline was instilled into the eyes of rabbits. At predetermined time intervals after dosing, blood was withdrawn, rabbits were euthanized, and periocular tissues were dissected. Ocular instillation of the GFS resulted in higher concentrations of propranolol in the outer layers of both the upper and lower eyelids (in the range of 9.9-36.9 μg/g) and maintained higher levels of propranolol in these tissues for 24 h after dosing, as compared to the ocular instillation of the non-GFS (in the range of 3.4-15.1 μg/g). While the concentrations of propranolol in the other periocular tissues were generally similar for GFS and non-GFS at 1 h after dosing, the concentrations of propranolol in the extraocular muscles and periocular fat were higher for GFS than those for non-GFS between 4-24 h after dosing. Lower level of propranolol in plasma was observed at 1 h with GFS as compared with non-GFS. The use of the propranolol gel-forming solution can prolong drug retention on the ocular surface and increase its distribution to the outer layers of the eyelids while decreasing systemic exposure to the drug.

Development of a MSFIA sample treatment system as front end of GC–MS for atenolol and propranolol determination in human plasma

An on-line solid-phase extraction (SPE) method coupled to gas chromatography–mass spectrometry (GC–MS) has been developed for the determination of atenolol (ATN) and propranolol (PRO) in human plasma. The hyphenation of SPE with multisyringe flow injection analysis (MSFIA) allows the simultaneous GC–MS determination of ATN and PRO with high selectivity and sensitivity. On-line preconcentration and derivatisation of the analytes were carried out by means of using restricted access materials (RAM) and microwave (MW) assisted derivatisation reactions with N-methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA)+1% trimethylchlorosilane (TMCS). Multivariate optimization was applied to optimize experimental conditions. The whole procedure comprising sample pretreatment and analyte determination took about 15min. However, the overlap of the automatic sample treatment with the GC separation increased the frequency to 7samplesh−1. The validated method was successfully applied to direct ATN and PRO determination in human plasma.

Enantioseparation and Determination of Propranolol in Human Plasma on a New Derivatized β-Cyclodextrin-Bonded Phase by HPLC

A 6-azido-β-cyclodextrin was synthesized and derivatized with p-nitrophenyl isocyanate as chiral ligand. Then the ligand was chemically bonded to mesoporous SBA-15 via a ‘Click Chemistry’ reaction of the azido group with alkynyl group. A new p-nitrophenylcarbamoylated β-cyclodextrin bonded SBA-15 chiral stationary phase (NPCSP) for HPLC was thus obtained. The new stationary phase was first used for enantioseparation of propranolol in human plasma under the polar organic solvent mode. The effects of methanol content, concentration of glacial acetic acid/triethylamine in mobile phase and the temperature on the enantioseparation were studied in detail. The optimized chromatographic conditions were as follows: mobile phase was acetonitrile/methanol/glacial acetic acid/triethylamine (90/10/1.25/2.25, V/V) at 288 K, with a flow rate of 0.5 mL min−1, an injection volume of 20 μL and detection wavelength at 290 nm. The resolution was 2.04 with a short run time (< 15 min) under the optimal conditions. The content of propranolol in plasma was quantitatively measured by HPLC-MS under selected ion monitoring mode ([M + H]+ m/z 260.10) with hydrochlorothiazide as an internal standard. The good linear relationship was observed in the range of 2.5−50 μg L−1. The detection limits were 1 μg L−1 according to S/N = 3 for both enantiomers. The experimental results showed that the chiral stationary phase exhibited excellent chiral separation ability to propranolol. The analytical method for propranolol enantiomers was sensitive, accurate, simple and fast, which was can be for the determination of propranolol in plasma and related pharmacokinetic studies.

Quantification of propranolol in rat plasma by LC- MS/MS using tramadol as an internal standard: Application to pharmacokinetic studies in TAA-induced liver fibrotic rats

A simple, rapid and selective liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is developed and validated for quantification of propranolol without the sample extraction step in rat plasma using tramadol as an internal standard (IS). The analytes are separated using an isocratic mobile phase which consist of methanol and 10 mm ammonium formate (70/30, v/v) on an isocratic UK-C18 (Imtakt Unison 2.0 × 50 mm, 3 μm) column and was analyzed by MS/MS in the multiple reaction monitoring (MRM) mode using the transitions of respective (M+H)+ ions, m/z 260.0→116.2 and m/z 264.2→58.2 for quantification of propranolol and IS, respectively. The standard calibration curves showed good linearity within the range of 2.0 to 800.0 ng/ml (r2 = 0.999, 1/x2 weight). The lower limit of quantification (LLOQ) was 2 ng/ml. The retention time of propranolol and IS were 1.12 and 0.939 min which means that it is the potential for the high-through put potential of the proposed method. In addition, no significant metabolic compounds were found to interfere with the analysis. Acceptable precision and accuracy were obtained for the concentrations over the standard curve range. The validated method was successfully applied for the pharmacokinetic studies after 2 mg/kg of propranolol HCl in the thioacetamide (TAA)-induced fibrotic rats. Key words: Propranolol, liquid chromatography, mass spectrometry, pharmacokinetics, thioacetamide, liver fibrosis.

Effects of physiological and biochemical factors based on aging, pathological conditions and drug combinations on propranolol pharmacokinetics using physiologically-based pharmacokinetic model in humans

Sensitivity of physiological and biochemical parameters based on aging, pathological conditions and drug combinations on propranolol pharmacokinetics was investigated to define factors contributing to larger inter-individual variability on propranolol pharmacokinetics after oral administration than that after intravenous (iv) administration. Using a physiologically-based pharmacokinetic model, plasma propranolol concentration was simulated with wide-ranging physiological and biochemical parameters. Then calculated AUC and half-life (t1/2) were compared with those obtained from the basic condition. It was found that the total blood flow through the body (Qtot), hepatic volume, unbound fraction in the blood and metabolic parameters affected propranolol AUC. Except for Qtot, effects were greater with after oral administration than iv administration. The propranolol AUC decreased by half with a two-fold increase in hepatic volume after oral administration possibly because of the increased first-pass metabolism. By contrast, some distribution parameters such as the skin tissue-to-blood distribution ratio and blood-to-plasma concentration ratio affected propranolol t1/2. Finally, propranolol plasma concentrations were simulated in the case that metabolizing activity decreased to one half and one fifth with an assumption of metabolic enzyme inhibition. The simulated propranolol curves correlated well with the previously reported plasma concentration in the absence and presence of quinidine, which is well known to be a potent and selective CYP2D6 inhibitor. Thus, plasma propranolol pharmacokinetics was affected by parameters which related to the hepatic metabolism and the distribution, especially after oral administration.