Pharmacokinetics Of Propranolol Research Articles

Systemic exposure to propranolol in patients with chronic liver disease and its correlation with portal blood flow.

Propranolol is a beta-blocker used for the prevention of variceal bleeding in cirrhotic patients. We investigated the pharmacokinetics of propranolol in patients with chronic liver disease compared to that in healthy individuals. The relative amount of portal blood flow was measured to investigate the correlation of portal blood flow and the systemic exposure of propranolol. Thirty healthy subjects, 18 patients with chronic active hepatitis (CAH), and 54 patients with cirrhosis were included in this prospective study. Blood samples for pharmacokinetic analysis were taken up to 8 h post-dose. The portal blood flow was estimated by H/L ratio using thallium-201 (201TI) per rectal scintigraphy. A total of 78 subjects completed the study. The area under the concentration-time curve (AUC) to the last measurable time (AUClast, ng⋅h/mL) were 150.2 ± 154.1, 112.2 ± 84.7, and 204.0 ± 137.3 in healthy subjects, CAH patients, and cirrhosis patients, respectively. AUCrmlast showed positive correlation with the H/L ratio in patients with chronic liver disease (r = 0.5817, p < 0.0001). In conclusion, the patients with cirrhosis showed higher systemic exposure to propranolol than healthy subjects or patients with CAH. The increase in systemic exposure to propranolol was correlated with the decrease in portal blood flow.

Study of the pharmacokinetics of various drugs under conditions of antiorthostatic hypokinesia and the pharmacokinetics of acetaminophen under long-term spaceflight conditions.

To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions. The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied. The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in Vz for verapamil (-54Δ%), furosemide (-20Δ%), propranolol (-8Δ%), and acetaminophen (-9Δ%), but a statistically significant increase in Vz was found for etacizine (+39Δ%); there was an increasing trend in Clt for propranolol (+13Δ%) and acetaminophen (+16Δ%), and a decreasing trend in Clt for etacizine, verapamil, and furosemide (-22,-23 and-9Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13Δ%, respectively), propranolol and acetaminophen decreased (-5 and-12Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (-19 and-20Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26Δ%, respectively). A statistically significant decrease in AUC0-∞ (-57Δ%), Cmax (-53Δ%), relative bioavailability of acetaminophen (-52Δ%) and a sharp increase in Clt (+147Δ%), Tmax (+131Δ%) as well as a trend towards a significant decrease in T1/2 (-53Δ%), MRT (-36Δ%) and a moderate increase in Vz (+24Δ%) were found under control compared to background. Unidirectional changes in AUC0-∞, Clt, T1/2, MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for Cmax, Tmax, Vz were found in ANOH and SP compared to background studies. The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight.

Study of the pharmacokinetics of various drugs under conditions of antiorthostatic hypokinesia and the pharmacokinetics of acetaminophen under long-term spaceflight conditions.

To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions. The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied. The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in Vz for verapamil (-54Δ%), furosemide (-20Δ%), propranolol (-8Δ%), and acetaminophen (-9Δ%), but a statistically significant increase in Vz was found for etacizine (+39Δ%); there was an increasing trend in Clt for propranolol (+13Δ%) and acetaminophen (+16Δ%), and a decreasing trend in Clt for etacizine, verapamil, and furosemide (-22,-23 and-9Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13Δ%, respectively), propranolol and acetaminophen decreased (-5 and-12Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (-19 and-20Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26Δ%, respectively). A statistically significant decrease in AUC0-∞ (-57Δ%), Cmax (-53Δ%), relative bioavailability of acetaminophen (-52Δ%) and a sharp increase in Clt (+147Δ%), Tmax (+131Δ%) as well as a trend towards a significant decrease in T1/2 (-53Δ%), MRT (-36Δ%) and a moderate increase in Vz (+24Δ%) were found under control compared to background. Unidirectional changes in AUC0-∞, Clt, T1/2, MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for Cmax, Tmax, Vz were found in ANOH and SP compared to background studies. The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight.

Development and Evaluation of a Physiologically Based Pharmacokinetic Drug-Disease Model of Propranolol for Suggesting Model Informed Dosing in Liver Cirrhosis Patients.

AimThe study was aimed to understand the underlying causes for the differences in propranolol pharmacokinetics (PK) between healthy and cirrhosis populations by using a systematic whole-body physiologically based pharmacokinetic (PBPK) model-building approach for suggesting model informed propranolol dosing in liver cirrhosis patients with different stages of disease severity.MethodsA whole-body PBPK model was developed by using population simulator PK-Sim® by using reported physicochemical and clinical data for propranolol in healthy and liver cirrhosis populations. The model evaluation was done by visual verification and comparison of PK parameters using their observed/predicted ratios (Robs/pred).ResultsThe developed model has effectively described the disposition of propranolol after intravenous and oral application in healthy and liver cirrhosis populations. All the model predictions were comparable to the observed clinical data and the Robs/pred for all the PK parameters were within a 2-fold range. A significant increase in plasma concentration of propranolol and decrease in drug clearance was observed in progressive stages of liver cirrhosis. The developed model after evaluation with the reported clinical PK data was used for suggesting model informed propranolol dosing in different stages of liver cirrhosis based on systemic unbound drug concentration.ConclusionThe developed PBPK model has successfully described propranolol PK in healthy and cirrhosis populations after IV and oral administration. The evaluated PBPK propranolol-cirrhosis model can have many implications in predicting propranolol dosing in liver cirrhosis patients with different stages of disease severity.

Physiologically Based Pharmacokinetic Modeling of Propranolol in Relation to CYP2D6 Genotypes

Propranolol, used to treat high blood pressure and irregular heart rate, is mainly metabolized by cytochrome P450 2D6 (CYP2D6) to 4‐hydroxypropranolol (4‐OHP) and CYP1A2 to N‐desisoprophylpropranolol (N‐DIP). Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique for predicting the absorption, distribution, metabolism and excretion (ADME) of synthetic or natural chemical substances in humans and other animal species. We investigated whether the pharmacokinetics of propranolol was altered by the different CYP2D6 genotypes in Korean subjects. Then, through in vitro study of propranolol, the metabolic capacity of propranolol was measured according to the CYP2D6 genotypes. And we developed the PBPK model of propranolol related to CYP2D6 genetic polymorphism. Twenty‐five volunteers were grouped as CYP2D6 *wt ⁄ *wt (*wt=1 or 2, n=7), CYP2D6 *1/ *10 (n=3), CYP2D6 *1 ⁄ *5 (n=4) and CYP2D6 *10 ⁄ *10 (n=11) according to their genotypes. Propranolol hydrochloride 40 mg (Pranol®) was administered orally once to each subject in these four groups. The CYP2D6 *1, CYP2D6 *10 and CYP1A2 *1 were incubated with 0.5–100 μM propranolol for 60 min at 37 □. Then the metabolites were extracted, and the concentration was analyzed by liquid chromatography‐mass spectrometry. PBPK modeling of propranolol was developed and optimized using PK‐sim® software. And, validation of PBPK model was conducted by comparing the predicted values with observed values from comparison the pharmacokinetic studies. In clinical data, AUCend, AUCinf, Cmax and oral clearance of propranolol were significantly different in CYP2D6 genetic polymorphism (P&lt;0.005, respectively). Depending on the physico‐chemical parameters and ADME of each genotype, PBPK model of propranolol was developed. For metabolism, input values of in vitro Vmax of 4‐OHP in the presence of recombinant enzyme for CYP2D6 *1, CYP2D6 *10, and CYP1A2 *1 were 2.41, 0.344 and 0.383 pmol/min/pmol, respectively. And, input values of Km of 4‐OHP for CYP2D6 *1, CYP2D6 *10, and CYP1A2 *1 were 2.852, 8.914 and 6.95 μM, respectively. Input values of in vitro Vmax of N‐DIP in the presence of recombinant enzyme for CYP2D6 *1, CYP2D6 *10, and CYP1A2 *1 were 9.782, 7.891 and 11.18 pmol/min/pmol, respectively. And, input values of Km of N‐DIP for CYP2D6 *1, CYP2D6 *10, and CYP1A2 *1 were 162.8, 339.1 and 158.4 μM, respectively. The AUCinf mean of simulated PBPK model were 111.77, 184.74, 296.13, 370.85 ng·h/ml in CYP2D6 *wt ⁄ *wt, CYP2D6 *1 / *10, CYP2D6 *1 ⁄ *5 and CYP2D6 *10 ⁄ *10, respectively. The developed PBPK model of propranolol successfully described the pharmacokinetics of each CYP2D6 genotype group and its simulated values were within acceptance criterion (99.998% confidence interval). These results will be beneficial in prescribing the appropriate dosage of propranolol considering inter‐individual differences through this mechanical approach. In addition, the PBPK modeling of propranolol in relation to CYP2D6 genotypes will be applicable to the treatment of various ethnic groups, ages, and patients. The observed and predicted pharmacokinetics for propranolol with acceptance criterion range in CYP2D6 genotype groups. Genotype Cmax (ng/mL) AUCend (ng*h/mL) AUCinf (ng*h/mL) Tmax (h) T1/2 (h) CYP2D6*wt/*wt (n=7) Observed 21.93±5.74 132.2±41.39 150.07±40.34 1.79±0.27 4.04±0.94 Predicted 30.70 111.53 111.77 1.90 2.83 Aceeptance range 14.49–33.19 80.79–216.30 98.09–229.60 1.41–2.27 2.80–5.84 CYP2D6*1/*10 (n=3) Observed 32.30±5.92 149.28±62.51 165.18±71.82 1.50±0.50 3.27±0.61 Predicted 34.74 181.01 184.74 1.95 4.37 Aceeptance range 20.66–50.51 55.55–401.16 59.36–459.66 0.68–3.33 2.08–5.14 CYP2D6*1/*5 (n=4) Observed 43.75±16.07 245.37±100.75 255.58±99.22 1.75±0.29 3.72±1.14 Predicted 51.88 286.96 296.13 1.95 5.02 Aceeptance range 20.51–93.32 105.85–568.78 115.06–567.70 1.23–2.48 1.96–7.06 CYP2D6*10/*10 (n=11) Observed 48.77±17.07 339.82±106.89 360.32±110.67 2.27±0.82 4.68±1.38 Predicted 62.70 357.72 370.85 2.00 5.14 Aceeptance range 31.51–75.48 229.04–504.19 245.02–529.88 1.45–3.56 3.23–6.78

Effect of Antiorthostatic Hypokinesia on the Pharmacokinetics and Bioavailability of Propranolol

The pharmacokinetics of propranolol were studied in healthy volunteers after a single peroral administration at a dose of 80 mg under normal conditions, on the second day of antiorthostatic hypokinesia, and on the first day after termination of the hypokinesia. The maximum propranolol concentration (–6 ∆%), area under the pharmacokinetic curve (–13 ∆%), elimination half-life (–15 ∆%), mean residence time in the body (–17 ∆%), and distribution volume (–8 ∆%) tended to decrease with antiorthostatic hypokinesia whereas the total clearance (+13 ∆%), ratio of maximum concentrations (125 ± 23%), and relative absorption rate of the drug (158 ± 48%) increased.

Propranolol pharmacokinetics in infants treated for Infantile Hemangiomas requiring systemic therapy: Modeling and dosing regimen recommendations.

Propranolol has become the first choice therapy for complicated Infantile Hemangiomas (IH). The pharmacokinetics of propranolol were evaluated after repeated oral administration of a new pediatric solution of propranolol at 3 mg kg−1 day−1 given twice daily (BID) in infants (77‐243 days) with IH. A population model was built to describe the pharmacokinetics of propranolol in infants and to simulate different dosing regimens. One hundred and sixty‐seven plasma concentrations from 22 infants were used in the population analysis. Weight effect was tested on apparent clearance and volume of distribution. Monte‐Carlo simulations were performed for 4 dosing regimens: BID dosing with irregular or strict 12‐hour intervals and 2 different 3 time daily dosing (TID) regimens. The best model was a one‐compartment model with first‐order absorption and elimination rates. The weight affected the clearance but not the volume. Typical oral clearance was estimated at 3.06 L hour−1 kg−1 (95% CI: 1.14‐8.61 L hour−1 kg−1), close to adult clearance data. When regular BID dosing was compared to TID or irregular BID regimens, simulated median Cmin and Cmax were <20% different. To conclude, a model using a weight allometric function on clearance was established and confirmed that the dose in mg/kg should be used without adaptation by range of age in treatment of complicated IH. The simulations support the use of a BID dosing preferably to a TID dosing thanks to close Cmin and Cmax at steady state between both regimen and showed the possibility of irregular BID dosing, allowing early administration in the evening when needed.

PROPRANOLOL PHARMACOKINETICS AND HEMODYNAMIC INDICES IN ANTIORTHOSTATIC HYPOKINESIA.

Purpose of the work was to study pharmacokinetics of beta adrenoblocker propranolol, and hemodynamic indices in volunteers for simulation of some effects of microgravity The study involved 8 essentially healthy subjects and the head-down tilt (-80) bedrest model reproducing the effects of microgravity (BD). This was designed as three series of investigations, i.e. before BD, on BD day-2 and on the first day of BD completion. Propranolol concentration in blood plasma was determined using high performance liquid chromatography with fluorescence detection. Hemodynamic indices including heart rate (HR), stroke volume, cardiac output, cardiac index and total peripheric resistance were measured using integral rheography; average blood pressure (BPav) Was assessed by Korotkovs method. Statistical deviations in propranolol pharmacokinetics were found in none of the three series. The most characteristic reactions to propranolol were BPav reductions in all series and HR decreases 2 hours after intake in the first and second series. These deviations were not pathologic but physiological variations typical of healthy people. Therefore, propranolol can be advised for rational pharmacotherapy of acute cardiovascular diseases in piloted space missions.

Effects on Pharmacokinetics of Propranolol and Other Factors in Rats After Acute Exposure to High Altitude at 4,010 m.

A series of pathological, physiological, and biochemical changes, even anatomical histological changes happen while humans arrive at the high plateau region from plain area. There is a certain relationship between the body's compensatory or decompensated adjustments to the environment and the changes of absorption, distribution, metabolism, and excretion of drugs. The objective of the study is to observe the effects of acute exposure to high altitude at 4,010 m on pharmacokinetics of propranolol in rats, and to provide basis and new ideas to adjust drug dosage and administration, so as to promote rational drug use in high altitude. 28 healthy male wistar rats were randomly divided into four groups, group A and B which were in plain area; group C and D which were acutely exposed to high altitude by aviation; group A and C were used for pharmacokinetics determination of propranolol, while group B and D had no drug administration for physiological and pathological changes research at high altitude. The pharmacokinetics of propranolol significantly changed; area under curve, C max (the peak concentration), mean residence time, and t 1/2 (the biological half-life) increased significantly by 481.72, 398.94, 44.87, and 58.77 %, respectively; clearance and V (apparent volume of distribution) decreased by 81.50 and 70.56 %, respectively, after acute exposure to high altitude at 4,010 m; Analytic results show that pH, buffer base, base excess, ctCO2 (content of total carbon dioxide), sO2 (oxygen saturation of arterial blood), pO2 (oxygen tension of arterial blood), and cNa(+) severely decreased by 2.43, 630.00, 311.00, 11.48, 91.38, 76.22, and 2.82 %, respectively, while pCO2 (carbon dioxide tension of arterial blood) and cCl(-) significantly increased by 47.40 and 6.76 %. Lactate dehydrogenase and total protein significantly decreased by 58.44 and 26.82 %, while total bilirubin and alkaline phosphatase severely increased by 338 and 24.94 % after acute exposure to high altitude at 4,010 m. Pathological research shows that alveolar wall is hyperemic, edematous, and incrassate; alveolus epithelium becomes hyperplastic while neutrophilic granulocytes infiltrate; brain neurons are edematous and perivascular space occurred; neurons of seahorse are metamorphic and karyopyknotic; mesangial cells are hyperplastic in kidney glomerulus tissue. We should reduce the dosage or extend the dosing interval in high altitude to maintain the drug concentration in therapeutic window since velocity of metabolism and excretion are reduced.

Effect of acute exposure to high altitude on the pharmacokinetics of propranolol

To study the pharmacokinetics of propranolol in Wistar rats after acute exposure to high altitude. Fourteen male Wistar rats (200±20) g were selected. After administration of propranolol tablets (0.05 g/kg, i.g.), blood samples (3 mL) were collected at 0, 20, 40 min,1, 1.5, 2, 4, 6, 8, 12 and 24 h, respectively. The pharmacokinetic parameters were determined by LC-MS/MS and DAS 2.0 software. The main pharmacokinetic area under concentration-time curve (AUC), mean retention time (MRT), half-life (t1/2) and peak plasma concentration (Cmax) of propranolol were increased by 442.61%, 47.45%, 73.13% and 352.97%, respectively, whereas Tmax and clearance (CL) were decreased by 80.87% and 68.94%, respectively. This study displays significant changes in the pharmacokinetics of propranolol under high altitude, which may provide evidence for clinical rational application of propranolol at high altitude.

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.

Propranolol concentrations after oral administration in term and preterm neonates

Objective: While propranolol pharmacokinetics has been extensively studied in adults, this study reports the first evaluation of propranolol pharmacokinetics in term and preterm neonates.Methods: Propranolol concentrations were measured in four term and 32 preterm newborns treated with oral propranolol at the dose of 0.5 or 0.25 mg/kg every 6 h by serial dried blood spots.Results: The levels of propranolol, although with high inter-individual variability, were proportional with the administered dose. Pharmacokinetic parameters evaluated at the steady state in newborns treated with 0.5 mg/kg/6 h showed values of maximal (71.7 ± 29.8 ng/mL), minimal (42.2 ± 20.8 ng/mL) and average concentration (60.8 ± 25.0 ng/mL), time of maximal concentration (2.6 ± 0.9 h) and area under the time-concentration curve (364.7 ± 150.2 ng/mL/h) similar to those observed in adults. In both dosing groups, elimination half-life was significantly longer (14.9 ± 4.3 and 15.9 ± 6.1 h), and apparent total body clearance (27.2 ± 13.9 and 31.3 ± 13.3 mL/kg/min) lower than those reported in adults, suggesting a slower metabolism in newborns. No differences were observed between newborns with different gestational age or different sex.Conclusions: Neonates treated with propranolol-exhibited drug concentrations proportional with the dose, with significant long half-life.

Important details to be clarified about the effect of rectal ozone on the portal vein oxygenation

We read with interest the paper by Zaky et al. [1]. In this study, the results of the propranolol pharmacokinetics in cirrhotic patients show that after 14 rectal administrations of oxygen-ozone (300 ml of 40% ozone/oxygen mixture), all parameters of the drug's metabolism improve. However, in our opinion there are a few important details to be clarified: firstly, what is the real ozone dose, because the reported sentence ‘rectal ozone insufflation at a dose of 300 ml of 40% ozone/oxygen mixture’ means only that 120 ml ozone were in gas mixture, but unless the ozone concentration (usually expressed as µg ml–1) is defined, the actual dose remains unknown. Secondly, an increased oxygen tension and saturation in the portal vein have been found. Such a result agrees also with our experimental data previously performed in rabbits [2]. Nevertheless, gaseous ozone cannot be present as such in the portal vein because ozone is never absorbed after rectal administration by the colo-rectal mucosa, contrary to what happens to oxygen [2, 3]. What then is the role of ozone? Does ozone improve oxygen absorption by the mucosa or are the compounds generated by ozone reaction in the luminal content and mucosal surface to have a relevance in modifying the propranolol parameters? Indeed, the control experiment performed by the administration of either 180 ml or 300 ml oxygen only is critically missing. We have clarified that oxygen is the natural carrier but the reactive gas is ozone, which inside the rectal lumen very rapidly generates hydrogen peroxide and a variety of lipohydroperoxides and alkenals [4]. They are highly reactive and rather than oxygen, may well be responsible for the modified propranolol pharmacokinetics, but they have been neither mentioned nor apparently measured. In our experiments these compounds were significantly present in portal blood and far less, as expected, in the jugular vein. To date, on the basis of our knowledge, rectal insufflation of 200–300 ml of an oxygen-ozone mixture (maximum ozone concentration 35 µg ml–1, hence an ozone dose of 7–10 mg per treatment) in liver cirrhosis may be a little helpful but cannot modify the prognosis. We hope that our comments will be useful for further studies.

Comparison of the Pharmacokinetics of Intravenous and Oral Propranolol in Obese and Normal Volunteers

Comparison of the Pharmacokinetics of Intravenous and Oral Propranolol in Obese and Normal Volunteers Get access S L Bowman, S L Bowman Department of Pharmacy, Heriot-Watt University and Eastern General Hospital, Edinburgh Search for other works by this author on: Oxford Academic Google Scholar S A Hudson, S A Hudson Department of Pharmacy, Heriot-Watt University and Eastern General Hospital, Edinburgh Search for other works by this author on: Oxford Academic Google Scholar J F Munro, J F Munro Department of Pharmacy, Heriot-Watt University and Eastern General Hospital, Edinburgh Search for other works by this author on: Oxford Academic Google Scholar G Simpson, G Simpson Department of Pharmacy, Heriot-Watt University and Eastern General Hospital, Edinburgh Search for other works by this author on: Oxford Academic Google Scholar J A Clements J A Clements Department of Pharmacy, Heriot-Watt University and Eastern General Hospital, Edinburgh Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 37, Issue Supplement_12, December 1985, Page 39P, https://doi.org/10.1111/j.2042-7158.1985.tb14111.x Published: 12 April 2011

The effect of rectal ozone on the portal vein oxygenation and pharmacokinetics of propranolol in liver cirrhosis (a preliminary human study)

The aim of this study was to investigate the effect of rectal ozone on portal vein oxygenation and the pharmacokinetic changes of propranolol in patients with liver cirrhosis. Fifteen patients with liver cirrhosis were included They were given a fixed oral dose of propranolol 80mg on the morning of day 1 after overnight fasting. Blood samples were collected at fixed time intervals for 24h. Patients were given 12 sessions of rectal ozone of 300ml of 40% ozone/oxygen mixture. On day 14 another oral dose of 80mg propranolol was given and blood samples were collected as on day 1. Plasma concentrations of propranolol were measured by HPLC. Portal vein oxygen tension and saturation were measured before and after rectal ozone. Plasma concentrations of propranolol were reduced after ozone therapy with pronounced decreases in the maximum plasma concentration and the area under the plasma concentration-time curve. The changes were consistent with a decrease in propranolol bioavailability. There was a decrease in the elimination half-life and mean residence time. Portal vein oxygenation significantly increased after rectal ozone. The changes in the pharmacokinetics of propranolol probably reflect an increase in the rate and extent of its metabolism resulting from improved portal vein oxygenation attributable to the ozone therapy. The present work highlights that ozone can be an alternative medical measure to improve portal vein oxygenation in liver cirrhosis.

Pharmacodynamic and Pharmacokinetic Interactions of Propranolol with Garlic (Allium sativum) in Rats.

Garlic preparations and propranolol (PRO) are agents recognized as cardioprotective and potent antihypertensive agents when they are used individually. However, there is no report available to explain the role of combined therapy during simultaneous hypertension and myocardial damage in rats. We aimed to determine the pharmacokinetic and pharmacodynamic interaction of PRO with garlic homogenate (GH), in rats. The influence of garlic on pharmacokinetics of PRO was determined by HPLC method; while pharmacodynamic interaction was studied in animals with hypertension (10% fructose) and myocardial damage (isoproterenol, 175 mg kg−1, s.c. 2 days). PRO was given orally at 10 mg kg−1 for 1 week, whereas, GH was administered at three different doses of 125, 250 and 500 mg kg−1, p.o. in their respective groups during fourth to sixth week of high fructose (HF) period, once daily. Systolic blood pressure (SBP), heart rate, cholesterol, triglycerides, glucose, creatine phosphokinase-MB, lactate dehydrogenase, superoxide dismutase and catalase were measured and histopathological studies were carried out. The bioavailability and half life of PRO were significantly enhanced by 2- and 3-fold, respectively, in animals pretreated with garlic (250 mg kg−1). Administration of PRO and low to moderate doses of GH (125, 250 mg kg−1), either alone or together showed fall in fluid intake and body weight. The combined therapy of GH 250 mg kg−1 and PRO was found to be most effective in reducing SBP, cholesterol, triglycerides and glucose. These observations suggest that careful addition of garlic in moderate doses in PRO regimen might result in beneficial effect during treatment of hypertensive animals with myocardial damage.

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.

Effect of cardiopulmonary bypass on the pharmacokinetics of propranolol and atenolol

The pharmacokinetics of some beta-blockers are altered by cardiopulmonary bypass (CPB). The objective of this study was to compare the effect of coronary artery bypass graft (CABG) surgery employing CPB on the pharmacokinetics of propranolol and atenolol. We studied patients receiving oral propranolol with doses ranging from 80 to 240 mg (N = 11) or atenolol with doses ranging from 25 to 100 mg (N = 8) in the pre- and postoperative period of CABG with moderately hypothermic CPB (32 degrees C). On the day before and on the first day after surgery, blood samples were collected before beta-blocker administration and every 2 h thereafter. Plasma levels were determined using high-performance liquid chromatography and data were treated by pharmacokinetics-modelling. Statistical analysis was performed using ANOVA or the Friedman test, as appropriate, and P < 0.05 was considered to be significant. A prolongation of propranolol biological half-life from 5.41 +/- 0.75 to 11.46 +/- 1.66 h (P = 0.0028) and an increase in propranolol volume of distribution from 8.70 +/- 2.83 to 19.33 +/- 6.52 L/kg (P = 0.0032) were observed after CABG with CPB. No significant changes were observed in either atenolol biological half-life (from 11.20 +/- 1.60 to 11.44 +/- 2.89 h) or atenolol volume of distribution (from 2.90 +/- 0.36 to 3.83 +/- 0.72 L/kg). Total clearance was not changed by surgery. These CPB-induced alterations in propranolol pharmacokinetics may promote unexpected long-lasting effects in the postoperative period while the effects of atenolol were not modified by CPB surgery.

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.

Induction of Propranolol Metabolism by Ginkgo biloba Extract EGb 761 in Rats

Ginkgo biloba is one of the most popular herbal medicines in the world, due to its purported pharmacological effects, including memory-enhancing, cognition-improving, and antiplatelet effects. When used in the elderly, Ginkgo has a high potential for interactions with cardiovascular drugs. This study aimed to investigate the effects of the standard Ginkgo biloba extract (EGB 761) treatment on the pharmacokinetics of propranolol and its metabolism to form N-desisopropylpropranolol (NDP) in rats. We also examined the activity and expression of cytochrome P450 (CYP) 1A and other CYPs in rats treated with EGb 761 at 10 and 100 mg/kg/day for 10 days. A single oral dose of propranolol (10 mg/kg) was administered on day 11 and the concentrations of both propranolol and NDP were determined using validated liquid chromatography-mass spectrometry (LC-MS) methods. The levels of mRNA and protein of various CYPs were determined by RT-PCR and Western blotting analysis, respectively. Pretreatment of EGb 761 at 100 mg/kg, but not 10 mg/kg, for 10 days significantly reduced the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of propranolol, whereas those values of NDP were significantly increased. CYP1A1, 1A2, 2B1/2, and 3A1 activities and gene expression in the rat liver were significantly increased in a dose-dependent manner by pretreatment with EGb 761. The ex-vivo formation of NDP in liver microsomes from rats pretreated with EGb 761 was markedly enhanced. The formation of NDP from propranolol in liver microsomes was significantly inhibited by alpha-naphthoflavone (ANF, a selective CYP1A2 inhibitor), but not by quinidine (a CYP2D inhibitor). These results indicated that EGb 761 pretreatment decreased the plasma concentrations of propranolol by accelerated conversion of parental drug to NDP due to induction of CYP1A2. EGb 761 pretreatment also significantly induced CYP2B1/2 and CYP3A1, suggesting potential interactions with substrate drugs for these two enzymes. Further study is needed to explore the potential for gingko-drug interactions and the clinical impact.