Increased Plasma Protein Binding Research Articles

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.

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.

Effects of acth and posture on aldosterone metabolism in essential hypertension

Timed urinary excretions of aldosterone 18-oxo-conjugate (oxo-c, a renal metabolite) and tetrahydro-aldosterqne glucuronide (THA-g, a hepatic metabolite) in response to posture and an 8-h infusion of ACTH were measured in control subjects and in patients with stable and labile essential hypertension. In patients with labile and also those with stable hypertension, the mean 4-h excretion of oxo-c, with subjects in the recumbent posture, was significantly greater and that of THA-g slightly less than in controls, while during upright posture the excretion rate of oxo-c declined much more in patients with both types of hypertension man in controls. ACTH infusion caused a greater increase in oxo-c excretion and a lesser increase in THA-g excretion during the subsequent 24 h in those with stable hypertension than in controls. These findings suggest that hepatic metabolism of aldosterone is relatively lower in both stable and labile essential hypertension, as supported by evidence of increased plasma protein binding and a comparatively lower metabolic clearance rate of aldosterone in some subjects. Furthermore, these altered patterns of aldosterone metabolite excretion in both stable and labile essential hypertension suggest that they may be the forerunner of established hypertension.

A Study of the Endocrine Manifestations of Hepatic Cirrhosis

The clinical features and hormonal abnormalities were surveyed in 117 men with cirrhosis of the liver. Compared with healthy men of similar ages, the patients had significantly lower metabolic clearance rates, plasma production rates and total and free levels of testosterone, reduced testosterone responses to human chorionic gonadotrophin stimulation, higher oestradiol, luteinizing hormone and follicle stimulating hormone levels and higher binding capacities of sex steroid binding globulin. The peripheral conversion of testosterone to oestradiol was also found to be significantly increased. However, the metabolic clearance and plasma production rates of oestradiol were not significantly different from those of healthy men. Patients who were severely ill with liver failure and one with haemochromatosis had low levels of luteinizing hormone and follicle stimulating hormone and sub-normal responses to clomiphene and luteinizing hormone-releasing hormone. Higher plasma oestradiol levels were found in patients with gynaecomastia and spider naevi than in those without these signs. However, the clinical features of androgen deficiency—that is, testicular atrophy, impotence and loss of secondary sex hair—were only poorly related to the low testosterone levels, and production rates and longtitudinal studies indicated that the hormonal levels, endocrine features and severity of the liver disease could change independently. It is concluded that the clearance of oestradiol from plasma is not limited by liver disease in all patients, and that reduced degradation of oestrogens is not the initial event in the sequence leading to the hormonal abnormalities of cirrhosis. While gonadotrophin deficiency occurs with liver failure and in some patients with haemo-chromatosis, the more usual findings are of elevated gonadotrophin levels and a poor Leydig cell response to chorionic gonadotrophin. These suggest that the hypo-gonadism is primary in most patients with cirrhosis. The causes of the high oestradiol levels were not discovered. Increased peripheral conversion of precursors to oestradiol or increased testicular secretion of oestradiol are possibilities. The high binding capacities of sex steroid binding globulin were not significantly correlated with either the low testosterone or high oestradiol level and the cause of this abnormality remains uncertain. The low metabolic clearance rates of testosterone appeared to result from the increased plasma protein binding of testosterone. The discrepancies in the expected relationships between the hormone and clinical changes suggest that factors other than those studied are also involved in the genesis of the endocrine features of hepatic cirrhosis.

Increased Plasma Protein Binding and Lower Metabolic Clearance Rate of Aldosterone in Plasma of Low Cortisol Concentration

During ACTH or cortisol infusion in ten recumbent normal men taking dexamethasone, the metabolic clearance rate of aldosterone increased by 50% as plasma cortisol was raised from low (2 mug/dl) to high concentration (50 mug/dl). Since splanchnic blood flow did not change, a greater efficiency of removal of aldosterone must have occurred, by means of displacement of aldosterone from high-affinity sites on plasma protein. At 37 C, equilibrium dialysis of low-cortisol plasma showed one-third of plasma aldosterone bound to albumin, and 24 to 28% bound to higher-affinity sites on other protein. As plasma cortisol increased, a progressively smaller fraction was tightly bound, approaching zero as transcortin was saturated with cortisol. The addition of large amounts of aldosterone to low-cortisol plasma displaced 14C-cortisol from transcortin binding sites. The results support earlier evidence that a significant fraction of plasma aldosterone is bound to transcortin, from which it is readily displaced by cortisol, resulting in an increased metabolic clearance rate of aldosterone by making a larger fraction available for removal from plasma.

A Study of the Endocrine Manifestations of Hepatic Cirrhosis

The clinical features and hormonal abnormalities were surveyed in 117 men with cirrhosis of the liver. Compared with healthy men of similar ages, the patients had significantly lower metabolic clearance rates, plasma production rates and total and free levels of testosterone, reduced testosterone responses to human chorionic gonadotrophin stimulation, higher oestradiol, luteinizing hormone and follicle stimulating hormone levels and higher binding capacities of sex steroid binding globulin. The peripheral conversion of testosterone to oestradiol was also found to be significantly increased. However, the metabolic clearance and plasma production rates of oestradiol were not significantly different from those of healthy men. Patients who were severely ill with liver failure and one with haemochromatosis had low levels of luteinizing hormone and follicle stimulating hormone and sub-normal responses to clomiphene and luteinizing hormone-releasing hormone. Higher plasma oestradiol levels were found in patients with gynaecomastia and spider naevi than in those without these signs. However, the clinical features of androgen deficiency--that is, testicular atrophy, impotence and loss of secondary sex hair--were only poorly related to the low testosterone levels, and production rates and longtitudinal studies indicated that the hormonal levels, endocrine features and severity of the liver disease could change independently. It is concluded that the clearance of oestradiol from plasma is not limited by liver disease in all patients, and that reduced degradation of oestrogens is not the initial event in the sequence leading to the hormonal abnormalities of cirrhosis. While gonadotrophin deficiency occurs with liver failure and in some patients with haemochromatosis, the more usual findings are of elevated gonadotrophin levels and a poor Leydig cell response to chorionic gonadotrophin. These suggest that the hypogonadism is primary in most patients with cirrhosis. The causes of the high oestradiol levels were not discovered. Increased peripheral conversion of precursors to oestradiol or increased testicular secretion of oestradiol are possibilities. The high binding capacities of sex steroid binding globulin were not significantly correlated with either the low testosterone or high oestradiol level and the cause of this abnormality remains uncertain. The low metabolic clearance rates of testosterone appeared to result from the increased plasma protein binding of testosterone. The discrepancies in the expected relationships between the hormone and clinical changes suggest that factors other than those studied are also involved in the genesis of the endocrine features of hepatic cirrhosis.

The secretion and metabolism of cortisol and aldosterone in normal and in steroid-treated women.

ABSTRACT The secretion rate and the pattern of metabolism of cortisol and of aldosterone were studied in women receiving oral doses of Enovid, norethynodrel, ethynylestradiol 3-methyl ether (EE3ME) and progesterone. Enovid, norethynodrel and EE3ME each had a marked estrogenic effect on the metabolism of cortisol, namely, a raised plasma level and increased plasma protein binding of the hormone, with a decreased excretion of tetrahydrocortisone, tetrahydrocortisol and allotetrahydrocortisol. No change was observed in the relative amounts of these three metabolites excreted. The secretion rate of cortisol was significantly decreased in the subjects receiving Enovid, norethynodrel and EE3ME. Cortisol secretion and metabolism in subjects receiving progesterone was similar to that in control subjects, except for a small but significant increase in the excretion of unconjugated metabolites. Progesterone, Enovid, norethynodrel, and EE3ME in the higher dosage of 0.3 mg per day increased the secretion rate of aldo...