Plasma Propranolol Research Articles

Clinical Pharmacokinetics of Buffered Propranolol Sublingual Tablet (Promptol™)—Application of a New “Physiologically Based” Model to Assess Absorption and Disposition

Sublingual administration of certain buffered propranolol may improve the rate and extent of absorption compared to oral administration. The main objectives of this study were to (1) compare the plasma propranolol concentrations (Cp-prop) following sublingual administration of a specially buffered formulation (Promptol™) to that following oral administration of Inderal(®) and (2) evaluate the utility of a special pharmacokinetic model in describing the Cp-prop following sublingual administration. Eighteen healthy volunteers received 10mg sublingual Promptol™ or oral Inderal(®). Multiple Cp-prop were determined and their pharmacokinetics compared. Additional data following sublingual 40mg Promptol™ or Inderal(®) were utilized for evaluation of a special advanced compartmental absorption and transit (ACAT) model. For model simulation, the physicochemical parameters were imported from AMET predictor, whereas the pharmacokinetic parameters were calculated and optimized by Gastroplus(®). Based on this model, the quantity of drug absorbed via buccal/sublingual mucosa was estimated. Cp-prop was higher at earlier times with 3-fold greater relative bioavailability following sublingual Promptol™ compared to that from oral Inderal(®). The special ACAT model provided excellent goodness of fit of Cp-prop-time curve and estimated a 56.6% increase in absorption rate from Promptol™ and higher initial Cp-prop compared to the regular formulation. The modified ACAT model provided a useful approach to describe sublingual absorption of propranolol and clearly demonstrated an improvement of absorption of Promptol™. The sublingual 10mg Promptol™ achieved not only a similar systemic exposure as 30mg oral Inderal(®) but an earlier effective Cp-prop which may be advantageous for certain clinical conditions.

Multi-Dimensional Column Chromatographic Method with UV Detection, for the Determination of Propranolol at Therapeutic Levels in Human Plasma

A simple and rapid HPLC assay method for the estimation of propranolol (InderalR) in human plasma was developed and validated. The method totally eliminates the extraction procedure; sample clean-up was achieved by on-line solid-phase extraction. The separation was achieved with μBondapack 10 μm C18 column (octadecylsilane, 30 cm×3.9 mm). The mobile phase consisted of a mixture of water, methanol, acetonitrile, acetic acid and triethylamine in the proportion of 160 ml: 80 ml: 70 ml: 2.5 ml: 125 μl, respectively. The pH was adjusted to 3.4 using 1 N NaOH before the addition of triethylamine. The mobile phase was filtered (0.2 μm filter) and degasified in a ultrasonic bath. The mobile phase flow rate was 0.5 ml/min. Detection was by UV detector at 291 nm and the retention time (RT) observed at around 8 minutes. The recovery of the drug from plasma was assessed by comparing the peak height of the extracted plasma samples with the peak height of authentic (un-extracted) standards which were directly injected (i.e. without column switching) into the analytical column at these concentration levels. The recovery values showed differences lower than 4.0% between the added amount and the founded amount, and were independent of the concentration. The response was linear over a range of 20-100 ng/ml with a limit of detection of 1 ng/ml and limit of quantification at 8 ng/ml plasma. This limit of quantification is adequate for clinical analysis and pharmacotherapeutic studies and comparable to those values obtained by other workers. The same method was used for the bioavailability study of propranolol formulation in healthy, human and male volunteers.

Modification of propranolol’s bioavailability by Eurycoma longifolia water-based extract

Eurycoma longifolia (E. longifolia), a herb commonly consumed for its aphrodisiac properties, is widely used by Asian males. This may include hypertensive patients receiving propranolol which may cause sexual dysfunction as one of its side-effects. There is no published study of the potential pharmacokinetic interaction between propranolol and the herb. To study propranolol's pharmacokinetics when E. longifolia is consumed, comparing volunteers given either propranolol or a placebo. This is a placebo-controlled randomized single-blinded crossover study of the effect of a water-based extract of E. longifolia on the pharmacokinetics of a single dose of proporanolol (Inderal(®)) in 14 healthy non-smoker young males. Eighty milligram of propranonol was orally administered with (i) placebo (Lactose) or (ii) 200 mg of water-based extract of E. longifolia (0·0272 ± 0·0026%eurycomanone) following an overnight fasting. Blood samples were collected at 0, 0·5, 1, 1·5, 2, 3, 4, 6, 8 and 10 h for propranolol's plasma concentration determinations using a validated high-performance liquid chromatography (HPLC) method. When propranolol was administered with E. longifolia, its bioavailability (AUC0-∞) decreased by 29% while C(max) was reduced by 42% and T(max) was significantly prolonged by almost 86%. The terminal elimination half-life, however, was not significantly affected. The bioavailability of propranolol is significantly decreased when consumed together with E. longifolia. The interaction is due to a reduction in absorption, rather than an increase in propranolol's metabolism. Although the pharmacodynamics of propranolol was not affected in healthy volunteers, caution is still advisable with co-administration of the drug and the herb.

Quantitative determination of propranolol by ultraviolet HPLC in human plasma

Many previous published methods for the quantitative determination of propranolol (PRN) in human plasma have poor recoveries and were not validated according to the FDA guideline. The aim of this study is to develop a simple HPLC method for detecting PRN in human plasma and to validate it so that it can be applied to a clinical study. Chromatographic separation was achieved using a mixture of a mobile phase consisting of 160 ml water, 180 ml methanol, 70 ml acetonitrile, 2.5 ml acetic acid, and 125 µl triethylamine (v/v). The pH of the whole mixture was adjusted to 3.4. A flow rate of 0.5 ml/min was employed throughout with a 15 µl injection volume. Detection was done using a UV detector at 291 nm. The validated method was linear for concentrations ranging from 15–180 ng/ ml with a good separation and specificity for both PRN and its internal standard, oxprenolol (OXP), with excellent recoveries, precision, and accuracies. The limit of detection (LOD) and limit of quantification (LOQ) were 1 and 10 ng/ml, respectively. The stability studies demonstrated that PRN is stable in the autosampler vials and also up to 3.5 months. To the authors’ knowledge, the recovery, that ranged between 97.9–102.7%, is the highest among all previously reported methods that used HPLC with UV detection. The developed and validated method for PRN analysis is excellen,t and applicable to a clinical study.

Improving sublingual delivery of weak base compounds using pH max concept: Application to propranolol

The purpose of the present work was to provide theoretical and experimental support in generating an optimal pH (pH max) for a representative weak base compound (propranolol), that can lead to enhanced sublingual absorption. Initially equations for pH-solubility and pH-permeability profiles were derived and compared to the profiles obtained experimentally. Excellent correlation ( R 2 = 0.999) of solubility profiles was obtained using non-linear regression, and the permeability profiles further predicted that at certain pH (pH max), optimal mucosal permeation could be achieved. Subsequently, in a pharmacokinetics study, a buffered sublingual propranolol tablet, designed to achieve its pH max (when dissolved in saliva), were compared to that from a marketed product (Inderal ® which could not achieve pH max) in 8 healthy subjects. Each subject received the products sublingually for 15 min followed by swallowing the remaining drug–saliva. The plasma propranolol concentrations of AUC during first 30 min from the buffered tablet were significantly higher than that from the Inderal ® tablet ( p < 0.05), and no significant differences in the remaining AUC were observed. These in vitro and in vivo results on propranolol provided experimental confirmation of the pH max concept as well as its utility in sublingual drug delivery. Such an approach may be applicable to other similar compounds to improve sublingual drug delivery.

Chronic effects assessment and plasma concentrations of the β-blocker propranolol in fathead minnows ( Pimephales promelas)

The presence of many human pharmaceuticals in the aquatic environment is now a worldwide concern, yet little is known of the chronic effects that these bioactive substances may be having on aquatic organisms. Propranolol, a non-specific beta adrenoreceptor blocker (β-blocker), is used to treat high blood pressure and heart disease in humans. Propranolol has been found in surface waters worldwide at concentrations ranging from 12 to 590 ng/L. To test the potential for ecologically relevant effects in fish in receiving waters, short-term (21 days) adult reproduction studies were conducted, in which fathead minnows were exposed to nominal concentrations of propranolol hydrochloride [CAS number 318-98-9] ranging from 0.001 to 10 mg/L (measured concentrations typically from 78 to 130%). Exposure of fish to 3.4 mg/L (measured) over 3 days caused 100% mortality or severe toxicity requiring euthanasia. The most sensitive endpoints from the studies were a decrease in hatchability (with regard to the number of days to hatch) and a concentration-related increase in female gonadal somatic index (GSI), giving LOEC hatchability and LOEC female GSI values of 0.1 mg/L. Concentration-related decreases in weights of male fish were also observed, with LOEC male wet weight value of 1.0 mg/L, and the LOEC reproduction value was 1.0 mg/L. Collectively, these data do not suggest that propranolol was acting as a reproductive toxin. Plasma concentrations of propranolol in male fish exposed to nominal concentrations of 0.1 and 1.0 mg/L were 0.34 and 15.00 mg/L, respectively, which constitutes 436 and 1546% of measured water concentrations. These compare with predicted concentrations of 0.07 and 0.84 mg/L, and thus to a degree support the use of partition coefficient models for predicting concentrations in plasma in fish. In addition, propranolol plasma concentrations in fish exposed to water concentrations of 0.1 and 1.0 mg/L were greater than the human therapeutic plasma concentration and hence these data very strongly support the fish plasma model proposed by Huggett et al. [Huggett, D.B., Cook, J.C., Ericson, J.F., Williams, R.T., 2003a. A theoretical model for utilizing mammalian pharmacology and safety data to prioritize potential impacts of human pharmaceuticals to fish. Hum. Ecol. Risk Assess. 9, 1789–1799].

Simultaneous determination of propranolol and 4-hydroxy propranolol in human plasma by solid phase extraction and liquid chromatography/electrospray tandem mass spectrometry

A very sensitive, reliable, reproducible and highly selective assay for the simultaneous determination of free and total (conjugated and unconjugated) propranolol and its equipotent hydroxyl metabolite, 4-hydroxy propranolol, in human plasma was developed and validated. The analytes were simultaneously extracted from 0.300 mL of human plasma using solid phase extraction and detected in positive ion mode by tandem mass spectrometry with a turbo ionspray interface. Deuterium-labeled propranolol and 4-hydroxy propranolol, propranolol-d7 and 4-hydroxy propranolol-d7, were used as internal standards. The method has a lower limit of quantitation (LOQ) of 0.20 ng/mL for both analytes with the limits of detection (LOD) 50 and 100 pg/mL for propranolol and 4-hydroxy propranolol, respectively, based on a signal-to-noise ratio of 5. The assay was linear over a range 0.20–135.00 ng/mL for free propranolol and 0.20–25.00 ng/mL for free 4-hydroxy propranolol and linear over range 1.00–500.00 ng/mL for total propranolol and 1.00–360.00 ng/mL for total 4-hydroxy propranolol, with coefficient of determination greater than 0.99 for both analytes. The extraction recoveries were >96 and >64% on an average for propranolol and 4-hydroxy propranolol, respectively. The analytes were found stable in human plasma through five freeze (−15 °C)–thaw (room temperature) cycles and under storage on bench-top for at least 6.5 h, and also in mobile phase at 10 °C for at least 48 h. The method has shown tremendous reproducibility, with intra- and inter-day precision <11.3% (RSD), and intra- and inter-day accuracy <11% of nominal values, for both analytes, and has proved to be highly reliable for the analysis of clinical samples.

Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Propranolol in Human Plasma and its Application to a Bioequivalence Study

A rapid, sensitive, and specific method based on liquid chromatography/tandem mass spectrometry (LC-MS/MS) was developed and validated for the determination of propranolol in human plasma using metoprolol as internal standard. The drugs were extracted from plasma by liquid-liquid extraction and separated isocratically on a Phenomenex Synergi Fusion-RP C18 analytical column, 4 µm (150 mm × 4.6 mm i.d.) maintained at 30°C, with acetonitrile/water (95/5, v/v): 100 mM ammonium acetate: 100 mM acetic acid (65:15:20 v/v/v) as mobile phase, run at a flow rate of 1 mL min−1 (split 1:3). Detection was carried out by positive electrospray ionization (ESI +) in selected reaction monitoring (SRM) mode. The chromatographic separation was obtained within 3.0 min and was linear in the concentration range of 2–150 ng mL−1 (r2 = 0.9969). The method was successfully applied for the bioequivalence study of two tablet formulations (test and reference) of propranolol 80 mg after single oral dose administration to 36 healthy human volunteers, using an open, randomized, two period crossover design with one week wash out interval.The geometric means ratios of C max and AUC(0-∞) were 99.77 and 103.70%, respectively, with both the confidence intervals between 90.12–112.92% demonstrating the bioequivalence of the two formulations.

Analysis of hepatic metabolism affecting pharmacokinetics of propranolol in humans

We examined the metabolic kinetics of propranolol, constructed from saturable and non-saturable components, using liver microsomes. The metabolic activity in rat microsomes was much higher than that in human microsomes within the clinically observed plasma range. Using the physiologically based pharmacokinetic (PBPK) model incorporating the obtained metabolic parameters, the plasma kinetics of propranolol was well correlated with reported values, and then used to analyze the effect of hepatic first-pass metabolism on propranolol plasma pharmacokinetics in clinical doses. The simulated plasma concentrations and AUC values of propranolol increased proportionally to its dose; these levels were almost equivalent to intrinsic clearance (CL int1), presumed to be non-saturable. When Michaelis–Menten parameters were decreased to one twentieth, plasma concentrations slightly increased after 160 mg dosing. A similar result was obtained with steady-state plasma levels after repeated administration. On the other hand, the first-order absorption rate constant of propranolol did not affect AUC values. The dose-normalized AUC value started to increase about 10 3 mg dosing. When the dose exceed 10 6 mg dose, the CL int1 component hardly contributed to propranolol pharmacokinetics. Accordingly, under the conditions of the PBPK model, propranolol pharmacokinetics was considered to be dose-independent within the clinical dose range.

PROPRANOLOL PLASMA MONITORING IN CHILDREN SUBMITTED TO SURGERY OF TETRALOGY OF FALLOT BY A MICROMETHOD USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

To evaluate the analytical micromethod using liquid chromatography for the quantification of propranolol in children submitted to surgery of tetralogy of Fallot (TLF). Only 0.2 mL of plasma is required for the assay. Peaks eluted at 8.4 (Propranolol) and 17.5 min (verapamil, internal standard) from a C18 column, with a mobile phase 0.1 M acetate buffer, pH 5.0, and acetonitrile (60:40, v/v) at flow rate 0.7 mL/min, detected at 290 nm (excitation) and 358 nm (emission). Surgery was started 776 min of drug administration (8.7 mg, mean); seven blood samples were collected from six patients (4M/2F; 2.1 yrs;11.5 kg; 0.80 m; 18.9 kg/m(2)). Confidence limits of the method showed high selectivity and recovery, sensitivity of 0.02ng/mL, good linearity (0.05-1000 ng/mL), precision of 8.6% and accuracy of 3.1%. The mean duration of surgery was 283.2 min, with the patients remaining under cardiopulmonary bypass (CPB) for 114 min. A declining curve of propranolol plasma concentration was obtained after the last dose in the night that preceded the day of surgery. Plasma concentration also was normalized with hematocrit due to the hemodilution caused by the CPB procedure. On the other hand a decrease on drug plasma concentration was obtained between periods, the beginning of surgery to the postoperative day 2 (7.09 ng/mL and 0.05 ng/mL, p<0.05 respectively) and from the end of CPB to the postoperative day 2 (2.79 ng/mL e 0.05 ng/mL, p<0.05). Propranolol monitoring of plasma concentrations of children (TLF) normalized after the last preoperative dose revealed a decline from the beginning of surgery to the second postoperative day, suggesting that, once redistribution was restored, propranolol washout was complete.

On-line coupling of sequential injection extraction with restricted-access materials and post-column derivatization for sample clean-up and determination of propranolol in human plasma

The presented paper deals with a new methodology for direct determination of propranolol in human plasma. The methodology described is based on sequential injection analysis technique (SIA) coupled with solid phase extraction (SPE) column based on restricted access materials (RAM). Special RAM column containing 30 μm polymeric material— N-vinylacetamide copolymer was integrated into the sequential injection manifold. SIA–RAM system was used for selective retention of propranolol, while the plasma matrix components were eluted with two weak organic solutions to waste. Due to the acid–basic and polarity properties of propranolol molecule and principles of reversed-phase chromatography, it was possible to retain propranolol on the N-vinylacetamide copolymer sorbent (Shodex MSpak PK-2A 30 μm (2 mm × 10 mm)). Centrifuged plasma samples were aspirated into the system and loaded onto the column using acetonitrile–water (5:95, v/v), pH 11.00, adjusted by triethylamine. The analyte was retained on the column while proteins contained in the sample were removed to waste. Interfering endogenous substances complicating detection were washed out by acetonitrile–water (15:85), pH 11.00 in the next step. The extracted analyte was eluted by means of tetrahydrofuran–water (25:75), pH 11.00 to the fluorescence detector (emission filter 385 nm). The whole procedure comprising sample pre-treatment, analyte detection and column reconditioning took about 15 min. The recoveries of propranolol from undiluted plasma were in the range 96.2–97.8% for three concentration levels of analyte. The proposed SIA–RAM method has been applied for direct determination of propranolol in human plasma.

Concentration‐effect and dose‐response relations in clinical pharmacology

Concentration‐effect and dose‐response relations in clinical pharmacology

Human bioavailability of propranolol from a matrix-in-cylinder system with a HPMC-Gelucire® core

The bioavailability of propranolol from a matrix-in-cylinder system for sustained drug delivery, consisting of a hot-melt extruded ethylcellulose pipe surrounding a drug-containing HPMC-Gelucire® 44/14 core, was determined. An oral dose of 80 mg propranolol hydrochloride was administered to healthy volunteers ( n = 10) in a randomized cross-over study design either as a commercial pellet formulation (Inderal retard mitis®) or as a matrix-in-cylinder system. The influence of concomitant food intake on drug release from the matrix-in-cylinder system was also studied. During the first 10 h after administration, the matrix-in-cylinder system resulted in similar plasma levels as the reference formulation Inderal®. The concomitant intake of a high-fat, high-calorie breakfast did not cause dose-dumping. Between 10 h and 24 h after administration of the matrix-in-cylinder system, a remarkable increase of the propranolol plasma levels was noticed (compared to Inderal®). This effect was even more pronounced under fed conditions. The matrix-in-cylinder system had a relative bioavailability of 156% (fasted conditions) and 222% (fed conditions) compared to the marketed reference product. In order to elucidate the origin of this increased bioavailability, Caco-2 experiments and dog lymph studies were performed. However, none of these experiments was able to provide a conclusive answer.

Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery

The pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass (CPB), resulting in unpredictable postoperative hemodynamic responses to usual doses. The objective of the present study was to investigate the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting (CABG) by CPB under moderate hypothermia. We evaluated 11 patients, 4 women and 7 men (mean age 57 +/- 8 years, mean weight 75.4 +/- 11.9 kg and mean body surface area 1.83 +/- 0.19 m(2)), receiving propranolol before surgery (80-240 mg a day) and postoperatively (10 mg a day). Plasma propranolol levels were measured before and after CPB by high-performance liquid chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the pharmacokinetic parameters after administration of the drug pre- and postoperatively. There was an increase of biological half-life from 4.5 (95% CI = 3.9-6.9) to 10.6 h (95% CI = 8.2-14.7; P < 0.01) and an increase in volume of distribution from 4.9 (95% CI = 3.2-14.3) to 8.3 l/kg (95% CI = 6.5-32.1; P < 0.05), while total clearance remained unchanged 9.2 (95% CI = 7.7-24.6) vs 10.7 ml min(-1) kg(-1) (95% CI = 7.7-26.6; NS) after surgery. In conclusion, increases in drug distribution could be explained in part by hemodilution during CPB. On the other hand, the increase of biological half-life can be attributed to changes in hepatic metabolism induced by CPB under moderate hypothermia. These alterations in the pharmacokinetics of propranolol after CABG with hypothermic CPB might induce a greater myocardial depression in response to propranolol than would be expected with an equivalent dose during the postoperative period.

Screening for library-assisted identification and fully validated quantification of 22 beta-blockers in blood plasma by liquid chromatography–mass spectrometry with atmospheric pressure chemical ionization

A liquid chromatographic-mass spectrometric assay with atmospheric pressure chemical ionization (LC-APCI-MS) is presented for screening for, library-assisted identification (both in scan mode) and quantification (selected-ion mode) of the beta-blockers acebutolol, diacetolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carazolol, carteolol, carvedilol, celiprolol, esmolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, propranolol, sotalol, talinolol and timolol in blood plasma after mixed-mode (HCX) solid-phase extraction (SPE) and separation by reverse-phase liquid chromatography with gradient elution. The validation data were within the required limits. The assay was successfully applied to authentic plasma samples allowing confirmation of diagnosis of overdose situations as well as monitoring of patients' compliance.

Bioequivalence Study Of Propranolol Tablets

The purpose of this study is to compare the bioavailability of a test tablet of propranolol (RAZA propranolol, Pharmaniaga) against an innovator product (Inderal, Astra Zeneca). The study was performed in eighteen healthy male volunteers for a single 2 x 40 mg dose of propranolol tablets. The study design used was a randomized, double blind two-period crossover design. Blood samples were collected before and within 24 hours after drug administration and plasma propranolol concentration was determined using HPLC method. Statistical analysis of the propranolol data indicated that none of the accepted parameters for drug bioavailability (AUC0 to 24hr, AUC0 to ∞ ,tmax and Cp max ) were significantly different between treatments for the single dose data. Parameters of AUC0 to 24hr of 630.4±285.0 ng.hr/ml vs 635.6±351.0 ng.hr/ml, AUC0 to ∞ , 670.2+299.2 ng.hr/ml vs 685.0+350.2 ng.hr/ml, tmax 1.3±0.5 hr vs 1.6±0.8 hr and Cpmax 115.3±53.4 ng/ml vs 117.5±77.3 ng/ml were obtained with test and reference formulations respectively. The 95% confidence interval of the log of ratio of AUC0 to 24hr, AUC0 to ∞ and Cp max were within the range of 0.80-1.25. It can be indicated that the two tablet dosage forms (i.e. RAZA and Inderal) showed similar bioavailability and are therefore considered bioequivalent.

Screening for library-assisted identification and fully validated quantification of 22 beta-blockers in blood plasma by liquid chromatography–mass spectrometry with atmospheric pressure chemical ionization

A liquid chromatographic–mass spectrometric assay with atmospheric pressure chemical ionization (LC–APCI–MS) is presented for screening for, library-assisted identification (both in scan mode) and quantification (selected-ion mode) of the beta-blockers acebutolol, diacetolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, carazolol, carteolol, carvedilol, celiprolol, esmolol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, propranolol, sotalol, talinolol and timolol in blood plasma after mixed-mode (HCX) solid-phase extraction (SPE) and separation by reverse-phase liquid chromatography with gradient elution. The validation data were within the required limits. The assay was successfully applied to authentic plasma samples allowing confirmation of diagnosis of overdose situations as well as monitoring of patients’ compliance.

Obesity influences propranolol pharmacokinetics in patients undergoing coronary artery bypass grafting employing cardiopulmonary bypass

Propranolol plasma levels and kinetic disposition may be altered by hypothermic cardiopulmonary bypass (CPB-H). We investigated the potential influence of obesity on propranolol pharmacokinetics in patients undergoing coronary artery bypass grafting employing CPB-H. Fifteen patients, receiving propranolol perorally pre- (10-40 mg, 2-3 times a day) and post-operatively (10 mg, once a day) were distributed in two groups, based on body mass index (BMI), in obese (n = 9, BMI: mean 29.4 kg/m²) and non-obese (n=6, BMI: mean 24.8 kg/m²). A serial of blood samples was collected at the pre- and post-operative periods at time dosing interval (Ä); propranolol plasma levels were measured one day before and after surgery using a high performance liquid chromatographic procedure described previously. PK Solutions software 2.0 was applied to obtain pharmacokinetic parameters. No changes on kinetic parameters as biological half-life (t1/2, p = 0.0625, NS), volume of distribution (Vd/F, p=0.8438, NS) and plasma clearance (CL T/F, p = 0.1563, NS) were obtained for the non-obese patients, while a prolongation of t1/2 (3.2 to 11.2 h, p< 0.0039), an increase on Vd/F (3.0 to 7.7 L/kg, p<0.0039) and reduction on CL T/F (11.3 to 9.2 mL/min.kg, p<0.0391) were obtained in the post-operative period for obese patients. Pharmacokinetic data could justify propranolol plasma concentrations in obese patients higher than in non-obeses, after surgery.

Disease–drug interaction: Reduced response to propranolol despite increased concentration in the rat with inflammation

Inflammatory conditions reduce clearance, hence increase plasma concentration of drugs such as propranolol that are efficiently cleared by the liver. The therapeutic consequences of this increased plasma drug concentration is mainly unknown. However, for sotalol, another β-adrenergic antagonist, inflammation causes reduced potency. Sotalol, however, is renally cleared; hence, its clearance is unaffected by inflammation. We examined if the inflammation-induced increased plasma propranolol concentration compensates for the reduced responsiveness. A modified lead I ECG was used to record PR interval and heart rate (HR). ECG was monitored following oral administration of 3, 5, 10, 15, 20, 25, and 30mg/kg propranolol to both control and adjuvant arthritis (AA) rats. To confirm altered pharmacokinetics, single 25mg/kg doses of propranolol were administered to both AA and control rats, with an inserted cannula in their right jugular vein for serial blood sampling. As expected, AA caused a significant reduction in the propranolol oral clearance and subsequently substantial increases in plasma total and unbound drug concentration. Interestingly, however, despite the elevated propranolol concentrations, the effect on HR remained unchanged and the prolongation of PR interval was significantly reduced in AA compared with control rats. The reduced sensitivity to propranolol in AA rats is suggestive of altered β-adrenergic receptors function.

Use of a quadrupole linear ion trap mass spectrometer in metabolite identification and bioanalysis.

A new type of quadrupole linear ion trap mass spectrometer, Q TRAP trade mark LC/MS/MS system (Q TRAP trade mark ), was evaluated for its performance in two studies: firstly, the in vitro metabolism of gemfibrozil in human liver microsomes, and, secondly, the quantification of propranolol in rat plasma. With the built-in information-dependent-acquisition (IDA) software, the instrument utilizes full scan MS in the ion trap mode and/or constant neutral loss scans as survey scans to trigger product ion scan (MS(2)) and MS(3) experiments to obtain structural information of drug metabolites 'on-the-fly'. Using this approach, five metabolites of gemfibrozil were detected in a single injection. This instrument combines some of the unique features of a triple quadrupole mass spectrometer, such as constant neutral loss scan, precursor ion scan and multiple reaction monitoring (MRM), together with the capability of a three-dimensional ion trap. Therefore, it becomes a powerful instrument for metabolite identification. The fast duty cycle in the ion trap mode allows the use of full product ion scan for quantification. For the quantification of propranolol, both MRM mode and full product ion scan in the ion trap mode were employed. Similar sensitivity, reproducibility and linearity values were established using these two approaches. The use of the product ion scan mode for quantification provided a convenient tool in selecting transitions for improving selectivity during the method development stage.