Serum concentration and urinary excretion of3H-ouabain and3H-digitoxin in patients suffering from hyperthyroidism or hypothyroidism

Eickenbusch, W; Lahrtz, Hg.; Seppelt, U; Zwieten, P. A. van

doi:10.1007/bf01486435

Cited by 34 publications

(8 citation statements)

References 15 publications

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“…Compared with the numerous useful studies of the pharmacokinetics of digoxin and digitoxin in both experimental animals and man (41)(42)(43), relatively few studies dealing with ouabain have been published (1)(2)(3)44). The radioimmunoassay described here has therefore been used to define the pharmacokinetics of ouabain in dogs and in human subjects (45).…”

Section: Discussionmentioning

confidence: 99%

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Ouabain-specific antibodies: immunochemical properties and reversal of Na+, K+-activated adenosine triphosphatase inhibition

Smith¹

1972

J. Clin. Invest.

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A B S T R A C T Antibodies with high affinity and specificity for the cardiac glycoside ouabain were raised in rabbits. The antigen used was a conjugate of ouabain linked through its rhamnose moiety to terminal aamino groups of poly D,L alanyl-human serum albumin. Ouabain-specific antibodies were present as early as 3 wk, and rose steadily in titer over the initial 20-33 wk of immunization. Levels as high as 6.5 mg specific immunoglobulin per ml antiserum were reached in one rabbit at the end of 45 wk. The average intrinsic association constants for ouabain were 1.3 X 109 M-' and 1.6 X 109 m' in antisera studied in detail, and there was evidence of restricted heterogeneity of binding site affinities. A high degree of specificity was demonstrated.Significant cross-reactivity occurred only with other cardioactive steroid compounds such as acetyl strophanthidin, digoxin, and digitoxin, while endogenous steroids did not cross-react even when present in 1000-fold excess. A rapid and convenient radioimmunoassay procedure for plasma or urine ouabain concentrations was developed using these antibodies. Competition between ouabain-3H tracer and unlabeled ouabain for specific antibody binding sites allowed the measurement of ouabain concentrations as low as 0.1 ng/ml or less without need for extraction procedures. The high association constants observed in these studies permit antibody reversal of established myocardial effects of ouabain. Both blockade and reversal of ouabain inhibition of canine myocardial microsomal Na+, K+-activated ATPase by antibody were documented, suggesting a possible mechanism for reversal of cellular effects.Dr. Smith is an Established Investigator of the American Heart Association.Received for publication 3 December 1971 and in revised form 27 January 1972. INTRODUCTIONThe rapidly acting cardioactive steroid glycoside ouabain has been widely used in both clinical and physiological investigations, as well as in the management of patients with congestive heart failure and certain cardiac rhythm disturbances. To the present time, however, the only means of quantitating the minute concentrations of the drug present in plasma or urine of animals or human subjects given usual pharmacologic doses has been the administration of tritiated ouabain (ouabain-3H) with subsequent measurement of radioactivity by liquid scintillation counting (1-3).This report describes the immunization of rabbits with a conjugate of ouabain covalently linked to poly D,L alanyl-human serum albumin. Ouabain-specific antisera obtained after this challenge were characterized in terms of affinity, heterogeneity, specificity, and time course of rise in titer. A specific and convenient radioimmunoassay was developed which permits the measurement of picomolar concentrations of ouabain in biological fluids including plasma and urine.The high association constants observed enhance the sensitivity of the assay and allow antibody reversal of established cellular effects of ouabain (4). In order to explore the mechanism of antibody rev...

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Section: Discussionmentioning

confidence: 99%

“…To the present time, however, the only means of quantitating the minute concentrations of the drug present in plasma or urine of animals or human subjects given usual pharmacologic doses has been the administration of tritiated ouabain (ouabain-3H) with subsequent measurement of radioactivity by liquid scintillation counting (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

Ouabain-specific antibodies: immunochemical properties and reversal of Na+, K+-activated adenosine triphosphatase inhibition

Smith¹

1972

J. Clin. Invest.

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“…Despite numerous studies (Shenfield 1981), there is still some disagreement with regard to effect on digoxin elimination. While some authors have found an increased renal elimination of digoxin (Bonelli et al 1978;Croxon & Ibbertson 1975;Eichenbusch et al 1970;Gilfrich 1976) and changes in glomerular filtration rate have correlated with renal digoxin elimination, there is not always a good correlation between renal and extrarenal digoxin clearance and thyroid status in individual patients (Lawrence et al 1977). Thus, confounding effects of impaired digoxin absorption and alterations in distribution and muscle binding may complicate the evaluation.…”

Section: Renal Clearancementioning

confidence: 92%

Clinical Pharmacokinetics and Endocrine Disorders Therapeutic Implications

O’Connor

Feely

1987

Clinical Pharmacokinetics

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Endocrine disorders are common and produce widespread changes in cellular and organ function. Alterations in the sensitivity of patients with thyroid disorders to digoxin, anticoagulants and sedatives have been recognised for many years. Many of the recently documented kinetic alterations in endocrine patients are explicable on the basis of disease-induced changes in hepatic drug metabolism, protein binding and renal function. In hyperthyroidism the rate of absorption of paracetamol, propranolol and oxazepam is increased due to increased gastrointestinal motility. The volume of distribution of propranolol and digoxin is increased and there is decreased binding of both basic and acidic drugs as a consequence of alterations in alpha 1-acid glycoprotein and albumin concentration. The rate of glucuronidation of paracetamol and oxazepam is increased in hyperthyroidism. While oxidative metabolism of antipyrine, propranolol, metoprolol and theophylline is enhanced, the clearance of a number of other agents, including diazepam, warfarin, antithyroid drugs and phenytoin, is unaltered. The systemic clearance of propranolol is enhanced as a consequence of a 50% increase in liver blood flow. The rate of elimination of a number of endogenous substances, including cortisol, thyroid hormones and insulin, also appear to be enhanced. Hyperthyroidism has a variable effect on renal function, with a possible increase in digoxin elimination, but no effect on the clearance of renally excreted beta-blockers, atenolol, sotalol and nadolol. These kinetic changes suggest that individualization and higher than normal dosage of propranolol is necessary to control hyperthyroidism, and in thyrotoxic atrial fibrillation higher doses of digoxin or additional therapy with beta-blockers, or verapamil, may be indicated. The increased sensitivity of thyrotoxic patients to warfarin suggest care with dosage and frequent monitoring of response are warranted. Less information is available concerning hypothyroidism, but there is a general trend for decreased absorption of paracetamol and propranolol. In addition, the volume of distribution of digoxin is reduced, as is renal clearance. Limited studies suggest no alteration in the glucuronidation of oxazepam, but antipyrine clearance appears to be reduced. Steady-state propranolol concentrations are elevated in hypothyroidism and there appears to be a decreased metabolism of thyroid hormones and cortisol. Preliminary information suggests the binding of propranolol is increased. Thus, in the treatment of hypothyroid patients, a lower dosage of propranolol may be required.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Thus, hyperthyroidism and hypothyroidism are associated with increased and decreased tolerance, respectively, to the cardiac effects of digitalis (1)(2)(3). The mechanism of altered digitalis sensitivity has been attributed in part to changes in pharmacokinetic disposition of glycosides, since significantly higher serum levels of glycosides were found in patients with hypothyroidism than in patients with hyperthyroidism following administration of identical doses (4,5). These differences in serum levels of cardiac glycosides appear to be accounted for by changes in distribution volume and in renal clearance (5-7).…”

Section: Introductionmentioning

confidence: 99%

Effects of thyroid hormone on sodium pump sites, sodium content, and contractile responses to cardiac glycosides in cultured chick ventricular cells.

Kim¹,

Smith²

1984

J. Clin. Invest.

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Abstract. Sensitivity of cardiac muscle to digitalis glycosides depends on the thyroid state. The mechanism of this interaction was investigated at the cellular level using spontaneously beating monolayers of cultured chick embryo ventricular cells. Cells were grown for 48 h in serum-free medium containing concentrations of triiodothyronine (T3) from zero to 10-7 M, and the total number of sodium pump sites, sodium content, and contractile amplitude in the presence and absence of various concentrations of ouabain were determined. T3 caused a concentration-dependent increase in the number of specific ouabain binding sites; the maximal increase to 160% of control was observed in response to 10-8 M T3. T3 lowered steady-state cellular sodium content in a concentration-dependent manner, also. Ouabain (1 ,uM) exposure elevated cellular sodium content in all cells, but the increase was greatest in cells grown in T3-free medium and least in cells grown in 10-8 M T3. The positive inotropic and toxic effects of ouabain in cells grown in 10-8 M T3 were diminished at any given ouabain concentration, and thus, the dose-response curve was shifted to the right. These results indicate that T3 causes induction of additional sodium pump sites that are functional. The increased tolerance of hyperthyroid cells and reduced tolerance of hypothyroid cells to cardiac glycosides can be explained by these changes in the number of sodium pump sites and cellular sodium

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Serum concentration and urinary excretion of3H-ouabain and3H-digitoxin in patients suffering from hyperthyroidism or hypothyroidism

Cited by 34 publications

References 15 publications

Ouabain-specific antibodies: immunochemical properties and reversal of Na+, K+-activated adenosine triphosphatase inhibition

Ouabain-specific antibodies: immunochemical properties and reversal of Na+, K+-activated adenosine triphosphatase inhibition

Clinical Pharmacokinetics and Endocrine Disorders Therapeutic Implications

Effects of thyroid hormone on sodium pump sites, sodium content, and contractile responses to cardiac glycosides in cultured chick ventricular cells.

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