Protein Binding Of Propranolol Research Articles

Alteration in plasma protein binding properties of propranolol and flurbiprofen during development of adjuvant-induced arthritis in rats

Adjuvant-induced arthritis (AA) in the rat is used as a model for rheumatoid arthritis. In AA rats, the pharmacokinetics of various drugs is affected due to the alterations of plasma protein binding of drugs. We choose propranolol (PL) and flurbiprofen (FP) as model basic and acidic drugs, respectively, and investigated the effect of AA induction on their plasma protein binding at each developing stage of inflammation. The plasma protein binding of PL and FP was dramatically changed due to reduced albumin and increased α1-acid glycoprotein levels for at least 21 days after adjuvant treatment. Moreover, we illustrated the differences in protein binding in AA between both the drugs in each developing stage of inflammation. These results suggest that the changed plasma protein levels in AA rats accompanying the altered protein binding of drugs affect the pharmacokinetics of drugs which extensively bind to plasma protein under inflammatory condition.

Propranolol Disposition in the Rat: Variation in Hepatic Extraction with Unbound Drug Fraction

The plasma protein binding of propranolol has been described as nonrestrictive for its hepatic extraction to explain the observation that propranolol is efficiently removed by the liver, in spite of extensive protein binding. The present study was designed to examine the relationship between propranolol protein binding, metabolism by isolated hepatocytes, and extraction by the isolated perfused rat liver. In isolated hepatocytes, the intrinsic clearance of free drug increased three-to fourfold as albumin and α1-acid glycoprotein (AAG) concentrations increased, suggesting that albumin and AAG facilitate the elimination of propranolol by hepatocytes. In the isolated perfused liver, propranolol extraction was almost complete (E = 0.996) in the absence of albumin and AAG. With 40 g/L of albumin and 2 g/L of AAG in the perfusate, the free fraction of propranolol decreased to 0.031, but extraction remained high (E = 0.960). With 40 g/L of albumin and 10 g/L of AAG in the perfusate, the free fraction further decreased to 0.014 and extraction dropped sharply (E = 0.820). The observed relationship between propranolol extraction and the free fraction of propranolol was in good agreement with that predicted using estimates of intrinsic clearance measured in isolated hepatocytes suspensions. These data indicate that propranolol extraction is sensitive to changes in binding at very low free fraction values and suggest a facilitation of propranolol clearance by albumin and AAG.

Effects of calcium channel blockers on the pharmacokinetics of propranolol stereoisomers

Diltiazem and verapamil inhibit oxidative drug metabolism both in vivo and in vitro. We compared their effects on the stereoselective pharmacokinetics and protein binding of propranolol in 12 subjects. After 6 days of coadministration with racemic propranolol, diltiazem caused decreases of 27% and 24% in d-propranolol and 1-propranolol oral clearances, respectively (p less than 0.05 versus control). With verapamil, d-propranolol oral clearance decreased 32% (p less than 0.05), and 1-propranolol oral clearance decreased 26% (p less than 0.05). The unbound fraction of d-propranolol was higher than that of 1-propranolol (p less than 0.05), but the protein binding was not altered by diltiazem or verapamil. Both drugs therefore decreased the unbound oral clearance of each propranolol enantiomer (p less than 0.05). Verapamil caused a stereoselective effect and increased the d/l ratio of propranolol serum concentrations (p less than 0.05) and decreased the d/l ratio of oral clearance (p less than 0.05).

Drug protein binding in chronic renal failure: Evaluation of nine drugs

In this study, changes of protein binding of nine drugs were evaluated. In addition, theophylline and phenytoin, the two drugs with the most substantial and progressive decrease in protein binding, were further studied by high performance liquid chromatography (HPLC)-fractions of ultrafiltrate of normal and uremic serum, in an attempt to identify substances causing drug protein binding inhibition. There was a marked decline of the protein binding of theophylline, phenytoin and methotrexate (dialyzed patients vs. normals: -20.1, -16.0 and -15.1%, respectively). There was a rise in the protein binding of propranolol, cimetidine and clonidine. The changes observed for diazepam, prazosin and imipramine were less marked. For phenytoin, theophylline, methotrexate and diazepam, protein binding was inversely correlated to the serum creatinine (r = 0.87, 0.80, 0.79 and 0.67, P less than 0.001), and a less pronounced but still significant positive correlation was found for clonidine (r = 0.46, P less than 0.01). Ultrafiltrate, obtained during a hemofiltration session, inhibited protein binding of theophylline and phenytoin in a dose dependent way. After separation of this ultrafiltrate by HPLC, it appeared that for both theophylline and phenytoin at least a part of this inhibitory activity corresponded to the elution zone of hippuric acid. For theophylline two other inhibitory zones were further recognized: one corresponding to the elution zone of NaCl and one in which the responsible substance remained unidentified. Hippuric acid in solution inhibited protein binding of theophylline and phenytoin in a dose dependent way. In conclusion, protein binding of several drugs currently used in renal failure is affected in parallel with renal function, which might affect the therapeutic effectiveness of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Propranolol Elimination as Described by the Venous Equilibrium Model Using Flow Perturbations in the Isolated Perfused Rat Liver

The kinetics of hepatic elimination of the high-clearance drug propranolol has been interpreted in a previous study from our laboratory, in which propranolol protein binding was varied, to conform to the venous equilibrium model. In another study by a different group, in which perfusate flow was varied, propranolol kinetics was interpreted to conform to the sinusoidal model. In the present study, we investigated the possibility that this discrepancy is due to the use of the two different discriminants, flow and protein binding, in the two studies. In eight livers, perfused in a recirculating design, steady-state elimination of propranolol (infused at a rate of 22.8 μg/min) was examined at perfusate flow rates of 16 and 32 mL/min. Hepatic outflow concentration was independent of perfusate flow rate, while the logarithmic average concentration was significantly lower at the higher flow. These data conform to the venous equilibrium model and are not consistent with the sinusoidal model. This shows that the outcome of these modeling experiments does not depend on the experimental approach used, and reaffirms that the venous equilibrium model is appropriate for propranolol under the conditions studied.

Effects of cancer and its treatments on plasma concentration of alpha 1-acid glycoprotein and propranolol binding.

The plasma concentrations of alpha 1-acid glycoprotein (AAG) and albumin, and the plasma protein binding of propranolol were measured in a group of cancer patients and a group of normal subjects. In cancer patients the AAG concentrations were twice that in controls (142 and 78 mg/dl, P less than 0.005), the albumin concentrations were lower (3.11 and 4.37 gm/dl, P less than 0.001), and the free fraction of propranolol was lower (0.127 and 0.190, P less than 0.005). Propranolol binding correlated strongly with AAG concentrations. These data imply that untreated or unsuccessfully treated cancer patients will have reduced free fractions for any drug for which AAG is an important binding protein. Successfully treated patients may have longitudinal changes towards normal. No consistent effect of the treatments themselves on AAG was observed after radiation therapy in five patients or after intravenous adriamycin in six patients.

Influence of Surgery on Plasma Propranolol Levels and Protein Binding

The influence of surgery and anesthesia on perioperative plasma propranolol levels was studied in 25 hyperthyroid and five euthyroid patients undergoing thyroidectomy. Propranolol levels fell markedly after surgery as a consequence of poor drug administration in the immediate postoperative period due largely to patients' nausea and inability to swallow. Propranolol was not detectable in the plasma of three hyperthyroid patients 8 hr after surgery. When propranolol was given through a nasogastric tube, propranolol levels were satisfactory throughout. Compared with preoperative levels, in all patients there was a two- to threefold rise in total and free propranolol levels 24 hr after surgery, suggesting decreased hepatic clearance of propranolol. The degree of plasma protein binding of propranolol had also increased on the day after surgery, leading to a 30% reduction in propranolol free fraction. Surgery and anesthesia greatly influence the handling of propranolol in the perioperative period. Clinical Pharmacology and Therapeutics (1980) 28, 759–764; doi:10.1038/clpt.1980.232