Plasma 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.

Plasma alpha 1-acid glycoprotein concentration in rats with chemical liver injury.

The influence of liver injury on the plasma concentrations of alpha 1-acid glycoprotein (AGP) and albumin was examined in several different models of chemically-induced liver injury. The plasma AGP concentration in carbon tetrachloride (CCl4), allyl alcohol, bromobenzene, acetaminophen or N-nitrosodimethylamine-induced liver injury was increased to 2-3.5 times the normal level at 24 h after the intoxication. The plasma AGP concentration was unchanged in ethionine-induced liver injury and was markedly decreased in galactosamine-induced injury. The plasma albumin concentration was significantly decreased by the damage due to galactosamine, allyl alcohol or N-nitrosodimethylamine-induced liver injury, while no influence was observed by other hepatotoxin-induced liver injury. The plasma protein binding of propranolol was also determined in relation to the plasma concentrations of AGP and albumin in all the experimental models. Propranolol binding, expressed as bound to free ratio, showed a good correlation with the AGP concentration (r = 0.940; p < 0.001), but not with the albumin concentration.

The inhibitory effects of cimetidine on elimination and distribution of propranolol in rats.

We studied the effects of cimetidine on the pharmacokinetics, blood and tissue distribution and plasma protein binding of propranolol in rats. The plasma disappearance of propranolol after a 10 mg/kg intravenous injection and oral administration were fitted to a two compartment open model. In the cimetidine treated rats, the area under concentration curve after an intravenous injection (AUCiv) was increased by 64% and the plasma total body clearance (Cltot) and the rate constant at the terminal phase (beta) were decreased by 38% and 33% of those of the non-treated rats, respectively. The area under the concentration curve after oral administration (AUCpo) was increased by 62% and the plasma oral clearance (Clpo) was decreased by 39% by cimetidine treatment, whereas the bioavailability (F) was not changed. The hepatic blood flow rate (Qh) and the product of the plasma unbound fraction and the hepatic intrinsic clearance (fp x Clint,h) calculated from Cltot and Clpo were decreased by 30% and 39%, respectively. The blood-to-plasma concentration ratio (Rb) and the tissue-to-plasma concentration ratio (Kp) of propranolol were not affected by cimetidine treatment, while the binding constant (Kb) in plasma was decreased by 45%. The plasma unbound fractions (fp) of propranolol were increased by 25-70% in the in vivo plasma concentration range (0.1-1.0 microgram/ml) resulting in the decrease of tissue-to-plasma unbound concentration ratio (Kp,u) in lung, heart, spleen, brain and muscle. Cimetidine was shown to have the inhibitory effects on elimination and distribution of propranolol in rats.

Increased availability of propranolol in rats with uranyl nitrate-induced acute renal failure.

The effect of acute renal failure (ARF) on the pharmacokinetics of propranolol was investigated. The model of ARF was produced by the subcutaneous injection of uranyl nitrate to rats (10 mg/kg) and was used 3 d after treatment. Uranyl nitrate-treated rats showed significantly higher plasma concentrations of propranolol after oral administration and the area under the plasma concentration-time curve increased about 3-fold compared to control rats. The plasma disappearance of propranolol after intravenous administration did not differ significantly between control and ARF. The mean availability of propranolol after oral administration increased from 0.120 in control to 0.215 in ARF (p less than 0.005). Absorption of propranolol was almost complete and no significant difference was found between two groups. No changes in plasma protein binding of propranolol and hepatic blood flow were observed in ARF. On the other hand, hepatic clearance of propranolol determined by liver perfusion studies showed a significant reduction in ARF and the calculated intrinsic clearance of unbound propranolol at a dose of 6.25 mg was 26.8 +/- 2.3 ml/min in control and 16.0 +/- 2.3 ml/min in ARF (p less than 0.01). These results demonstrate that the oral availability of propranolol increased in ARF due to a reduction in the hepatic presystemic elimination as compared to healthy control rats.

Clinical pharmacokinetics of beta-adrenoceptor blocking drugs in thyroid disease.

β-Adrenoceptor blocking drugs (β-blockers) have an established place in the management of patients with thyroid disease. Thyroid hormones, however, markedly alter hepatic, renal and cardiovascular function and thus may significantly influence drug disposition. In hyperthyroidism the clearance of propranolol following intravenous administration is increased by approximately 50%, an effect that may be attributed to the marked increase in liver blood flow that occurs in this condition. On the other hand, the increased clearance of propranolol during long term oral therapy is presumably due to increased hepatic drug metabolising enzyme activity. However, following single oral doses the clearance of propranolol has been reported both to be unchanged and increased in hyperthyroid patients. Both during single dose and long term therapy the elimination half-life of propranolol is unaltered, in part due to an increased apparent volume of distribution. The degree of plasma protein binding of propranolol appears to be slightly reduced in the hyperthyroid state.

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.

Intravenous propranolol in patients with inflammation.

British Journal of Clinical PharmacologyVolume 13, Issue 4 p. 577-578 Free Access Intravenous propranolol in patients with inflammation. DG Waller, DG WallerSearch for more papers by this authorCL Smith, CL SmithSearch for more papers by this authorAG Renwick, AG RenwickSearch for more papers by this authorCF George, CF GeorgeSearch for more papers by this author DG Waller, DG WallerSearch for more papers by this authorCL Smith, CL SmithSearch for more papers by this authorAG Renwick, AG RenwickSearch for more papers by this authorCF George, CF GeorgeSearch for more papers by this author First published: April 1982 https://doi.org/10.1111/j.1365-2125.1982.tb01426.xCitations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES De LEVE, L.D. & PIAFSKY, K.M. (1981). Pharmacokinetic consequences of variation in plasma propranolol binding due to rheumatoid arthritis. Clin. Pharmac. Ther., 29, 239– 240. McDEVITT, D.G., FRISK-HOLMBERG, M., HOLLIFIELD, J.W. & SHAND, D.G. (1976). Plasma binding and the affinity of propranolol for the beta receptor in man. Clin. Pharmac. Ther., 20, 152– 157. NATION, R.L., PENG, G.W. & CHIOU, W.L. (1978). High pressure liquid chromatographic method for the simultaneous quantitative analysis of propranolol and 4-hydroxy propranolol in plasma. J. Chromatog., 145, 429– 436. PARSONS, R.L., KAYE, C.M., RAYMOND, K., TROUNCE, J.R. & TURNER, P. (1976). Absorption of propranolol and practolol in coeliac disease. Gut, 17, 139– 143. PIAFSKY, K.M., BORGA, O., ODAR-CEDERLOF, I., JOHANSSON, C. & SJOQVIST, F. (1978). Increased plasma protein binding of propranolol and chlor-promazine mediated by disease-induced elevations of plasma aracid glycoprotein. New Engl. J. Med., 299, 1435– 1439. SCHNEIDER, R.E., BABB, J., BISHOP, H., MITCHARD, M., HOARE, A.M. & HAWKINS, C.F. (1976). Plasma levels of propranolol in treated patients with coeliac disease and patients with Crohn's disease. Br. med. J., 2, 794– 795. SCHNEIDER, R.E., BISHOP, H. & HAWKINS, C.F. (1979). Plasma propranolol concentrations and the erythrocyte sedimentation rate. Br. J. clin. Pharmac., 8, 43– 47. Citing Literature Volume13, Issue4April 1982Pages 577-578 ReferencesRelatedInformation

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

The influence of age, smoking and hyperthyroidism on plasma propranolol steady state concentration.

1 Plasma propranolol steady state concentration (Css) was determined during chronic dosage (160 mg/day) in 22 hyperthyroid patients (aged 16-75 years, 11 smokers, 11 non-smokers) and again following treatment when euthyroid. 2 There was a positive correlation between plasma propranolol Css and age in patients both when hyperthyroid (r = 0.74, P less than 0.01) and when euthyroid (r = 0.58, P less than 0.05). 3 Plasma propranolol Css in hyperthyroid patients were lower (P less than 0.05) in smokers than in non-smokers. 4 Following correction of hyperthyroidism there was a significant increase (P less than 0.01) in both the plasma propranolol Css and degree of plasma protein binding of propranolol. 5 Hyperthyroidism and smoking are known to increase the rate of drug metabolism and it is suggested that these variables may give rise to or accentuate an age related reduction in propranolol clearance.

Plasma propranolol steady state concentrations in thyroid disorders.

Plasma propranolol steady-state concentrations (Css) were measured in 24 hyperthyroid and 6 hypothyroid patients before and after correction of the thyroid disorder. Following treatment of hyperthyroidism by surgery, antithyroid drugs or radioiodine, there was a significant rise in the plasma propranolol Css in patients receiving propranolol either 160 mg/day, 240 mg/day, or 480 mg/day. In addition, in five patients the area under the plasma propranolol concentration versus time curve during a dosing interval increased significantly from 405 ng/ml/h when hyperthyroid to 778 ng/ml/h when euthyroid. In the hypothyroid patients given propranolol 160 mg/day concomitantly with 1-thyroxine therapy the plasma propranolol Css fell significantly when euthyroid. There was a small but significant increase in the degree of plasma protein binding of propranolol, following treatment of hyperthyroidism and a significant decrease following correction of hypothyroidism. It is concluded that thyroid disorders markedly influence propranolol handling.

Increased plasma protein binding of propranolol in rabbits with acute renal failure

Acute renal failure was produced in rabbits either by uranyl nitrate or by glycerol. Uremia ensued in all uranyl nitrate treated animals and in the majority of glycerol treated animals. In the uremic rabbits binding of phenytoin to plasma proteins decreased with respect to treated non-uremic animals and controls. On the other hand binding of propranolol markedly increased in uremia. The increased propranolol binding was not due to the elevated creatinine and urea levels in uremic plasma. Charcoal treatment of uremic plasma did not restore normal propranolol binding. The findings indicate that the influence of renal failure on binding of drugs to plasma proteins is more complex than hitherto assumed.

Altered plasma protein binding of drugs in thyroid disease.

The plasma protein binding of propranolol and warfarin was studied in vitro by ultrafiltration in hyper- and hypothyroid patients both before and after treatment. The degree of binding of propranolol was significantly decreased in hyperthyroid patients and increased in hypothyroid patients, and was negatively correlated with serum thyroxine and the free thyroxine index. The plasma protein binding of warfarin was also decreased in hyperthyroid patients, but was unchanged in hypothyroid patients. These results suggest that the binding of both acidic and basic drugs may be altered by thyroid disease.

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.

Prazosin protein binding in health and disease.

British Journal of Clinical PharmacologyVolume 9, Issue 2 p. 177-182 Free Access Prazosin protein binding in health and disease. P. Rubin, P. RubinSearch for more papers by this authorT. Blaschke, T. BlaschkeSearch for more papers by this author P. Rubin, P. RubinSearch for more papers by this authorT. Blaschke, T. BlaschkeSearch for more papers by this author First published: February 1980 https://doi.org/10.1111/j.1365-2125.1980.tb05830.xCitations: 18AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References BLASCHKE, T.F. (1977). Protein binding and kinetics of drugs in liver disease. Clin. Pharmacokin., 2, 32– 44. BORGA, O., AZARNOFF, D.L., FORSKELL, G.P. & SJÖQVIST, F. (1969). Plasma protein binding of tricyclic antidepressants in man. Biochem. Pharmac., 18, 2135– 2143. DROMGOOLE, S.H. (1973). The effect of hemodialysis on the binding capacity of albumin. Clin. Chimica Acta, 46, 469– 472. FRANKSSON, G. & ARGGARD, E. (1970). The plasma protein binding of amphetamine, catecholamines and related compounds. Acta Pharmac. tox., 28, 209– 214. FREMSTAD, D., BERGERUD, K., HAFFNER, J.F.W. & LUNDE, P.K.M. (1976). Increased plasma binding of quinidine after surgery: a preliminary report. Eur. J. clin. Pharmac., 10, 441– 444. HOBBS, D.S., TWOMEY, T.M. & PALMER, R.F. (1978). Pharmacokinetics of prazosin in man. J. clin. Pharmac., 18, 402– 406. KOCH-WESER, J. & SELLERS, E.M. (1976). Binding of drugs to serum albumin. New Engl. J. Med., 294, 311– 316, 526–531. OLSEN, G.D. (1972). Methadone binding to human plasma albumin. Science, 176, 525– 526. PIAFSKY, K.M., BORGA, O., ODAR-CEDERLOF, I., JOHNSSON, C. & SJÖQVIST, F. (1978). Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevation of plasma α1–acid glycoprotein. New Engl. J. Med., 299, 1435– 1439. REIDENBERG, M.M. (1976). The binding of drugs to plasma proteins from patients with poor renal function. Clin. Pharmacokin., 1, 121– 125. ROMER, J. & BICKEL, M.H. (1979). A method to estimate binding constants at variable protein concentrations. J. Pharm. Pharmac., 31, 7– 11. SCHMID, K. (1975). α1–acid glycoprotein. In The plasma proteins, ed. F.W. Putnam, 1, pp. 182– 228. New York: Academic Press. YEE, G., RUBIN, P. & MEFFIN, P. (1979). Prazosin determination by high pressure liquid chromatography using fluorescent detection. J. Chromatog., 172, 313– 318. Citing Literature Volume9, Issue2February 1980Pages 177-182 ReferencesRelatedInformation

Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma alpha1 acid glycoprotein.

To assess the importance of disease-induced increases in plasma concentrations of alpha1 acid glycoprotein (an acute-phase plasma protein that binds cationic drugs), we determined binding of propranolol in plasma from 53 patients and 25 healthy volunteers. Binding was increased in 10 patients with Crohn's disease (P less than 0.002), nine with inflammatory arthritis (P less than 0.002) and eight with chronic renal failure with superimposed inflammatory disease (P less than 0.01) as compared with healthy controls. The plasma binding of control subjects did not differ from that of 12 patients with chronic hepatic disease (P greater than 0.45) or 14 with uncomplicated renal failure (P greater than 0.80). Chlorpromazine binding, determined in 60 subjects, yielded similar results. Percentage of free drug and alpha1 acid glycoprotein concentration were inversely correlated (r = -0.77 with propranolol, P less than 0.001, and r = -0.69 with chlorpromazine, P less than 0.001). Increases in plasma protein binding in patients with inflammatory disease appear mediated by increases in alpha1 acid glycoprotein concentration, which may influence drug kinetics.

Plasma protein binding of propranolol and isoprenaline in hyperthyroidism and hypothyroidism.

1. The possibility that thyroid disease might result in alterations in the plasma proteins binding of drugs has been investigated by studying the binding of propranolol and isoprenaline in patients with hyperthyroidism and hypothyroidism. 2. Plasma protein binding of propranolol and isoprenaline has been measured in seven hyperthyroid patients and ten hypothyroid patients. Plasma binding was estimated by equilibrium dialysis at 37 degree C using triatiated propranolol and isoprenaline, both when the patients had thyroid dysfunction and again when they were euthyroid. 3. In the hyperthyroid group, mean propranolol binding varied from 86 +/- 1.7% when hyperthyroid to 88.4 +/- 0.8% when euthyroid. The comparable isoprenaline figures were 65.1 +/- 3.2% and 68.1 +/- 1.4% respectively. Neither difference was significant. 4. Isoprenaline binding was significantly lower (64.3 +/- 1.6%) when patients were hypothyroid than when they became euthyroid (68.8 +/- 1.2%). Propranolol binding was not altered by hypothyroidism. 5. It is concluded that clinically important alterations in free drug concentrations of propranolol or isoprenaline do not occur in hyperthyroidism or hypothyroidism.

Plasma protein binding of propranolol in disease states [proceedings

Plasma protein binding of propranolol in disease states [proceedings