Protein Binding of Disopyramide and Elevated Alpha-1-Acid Glycoprotein Concentrations in Serum Obtained from Dialysis Patients and Renal Transplant Recipients

Haughey, David B.; Kraft, Cheryl J.; Matzke, Gary R.; Keane, William F.; Halstenson, Charles E.

doi:10.1159/000166900

Cited by 39 publications

(18 citation statements)

References 11 publications

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“…These effects may be partially reversed by dialysis. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. CYP activity in the kidney is estimated to be 20% of liver activity per gram of tissue.…”

Section: Background Pharmacokineticsmentioning

confidence: 99%

“…Mechanisms point to circulating inhibitory factors some of which are dialyzable. Patients with advanced CRF Stage IV (GFR [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] and Stage V (0-15 ml/min) may behave differently depending whether or not they are on dialysis since these factors may be partially removed by dialysis. Estimating the magnitude of these nonrenal effects is difficult without empirical studies.…”

Section: Expert Opinionmentioning

confidence: 99%

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The effect of chronic renal failure on drug metabolism and transport

Dreisbach

Lertora

2008

Expert Opinion on Drug Metabolism & Toxicology

207

154

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Background-Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine.Objectives-The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport.Methods-The National Library of Medicine PubMed was utilized with the search terms 'chronic renal failure, cytochrome P450, liver metabolism, efflux drug transport and uptake transport' including relevant articles back to 1969.Results-Animal studies in CRF have shown a major downregulation (40-85%) of hepatic and intestinal cytochrome P450 (CYP) metabolism. High levels of parathyroid hormone, cytokines, and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein (Pgp) and organic anion transporting polypeptide (OATP) are also affected.Conclusion-CRF alters intestinal, renal, and hepatic drug metabolism and transport producing a clinically significant impact on drug disposition and increasing the risk for adverse drug reactions.

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Section: Background Pharmacokineticsmentioning

confidence: 99%

Section: Expert Opinionmentioning

confidence: 99%

The effect of chronic renal failure on drug metabolism and transport

Dreisbach

Lertora

2008

Expert Opinion on Drug Metabolism & Toxicology

207

154

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“…David et al (1983) further demonstrated prolonged variability in plasma protein binding in vitro from 20 patients with acute myocardial infarction with a relationship between the unbound DP fraction and plasma AAG concentration. The relationship between the binding of DP and the plasma AAG concentration was also demonstrated by Bredesen & Kierulf (1984) and Haughey et al (1985). Bredesen & Kierulf (1984) found a linear relationship between the AAG concentration and the binding ratio in plasma spiked samples.…”

Section: Resultsmentioning

confidence: 68%

Relationship between alpha 1‐acid glycoprotein and distribution of disopyramide and mono‐N‐dealkyldisopyramide in whole blood.

Bredesen¹,

Kierulf²

1986

Brit J Clinical Pharma

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The binding of disopyramide (DP) and mono‐N‐dealkyldisopyramide (MND) was measured by equilibrium dialysis in spiked whole blood (10 mumol l‐ 1 DP or MND) from 50 patients having a serum concentration of alpha 1‐ acid glycoprotein (AAG) ranging from 0.40 to 3.14 g l‐1, as well as in whole blood from five healthy subjects, spiked with different concentrations of AAG ranging from 0.61 to 3.33 g l‐1. The binding ratio (moles bound divided by moles unbound) in all samples increased from 1.0 to 8.0 for DP and 0.6 to 3.3 for MND with increasing AAG concentrations. The binding varied according to the AAG concentrations both in patients and healthy subjects. Similarly total and free plasma concentrations of DP and MND were also measured. With increasing AAG concentrations the total concentrations measured increased from 9.0 to 15.9 mumol l‐1 for DP and from 6.8 to 11.8 mumol l‐1 for MND whereas the free concentrations decreased from 3.8 to 0.5 mumol l‐1 for DP and from 5.0 to 2.0 mumol l‐1 for MND. With increasing AAG concentrations the whole blood/plasma concentration ratio decreased from 1.11 and 1.47 to 0.63 and 0.85 for DP and MND respectively. The ratio between their concentration in cells and the unbound concentration in plasma, however, was constant over the whole AAG concentration range. The mean ratios for all samples were 3.0 and 3.1 for DP and MND respectively, indicating that both compounds are bound or distributed to the blood cells. The distribution of the drugs in whole blood changed according to increasing AAG concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…The concentration of AAG, an acute phase reactant, is increased in patients with acute myocardial infarction (Piafsky et al 1980), chronic renal failure requiring dialysis, and renal transplant recipients (Haughey et al 1985). This results in reduction of the free fraction of disopyramide in these patients.…”

Section: Protein Bindingmentioning

confidence: 99%

Clinical Pharmacokinetics of Disopyramide

Siddoway

Woosley

1986

Clinical Pharmacokinetics

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Disopyramide is an antiarrhythmic agent with proven efficacy in the management of atrial and ventricular arrhythmias. The drug is well absorbed and undergoes virtually no first-pass metabolism. Peak concentrations are achieved approximately 0.5 to 3.0 hours after a dose. Absorption is reduced and slightly slowed in patients with acute myocardial infarction. Disopyramide is excreted as unchanged drug (two-thirds) or as the metabolite mono-N-desisopropyldisopyramide, with elimination via both renal and biliary routes. Elimination half-life is approximately 7 hours in normal subjects and patients, but is prolonged in patients with renal insufficiency (creatinine clearance less than 60 ml/min). Disopyramide exhibits complex protein binding. It is bound to alpha 1-acid glycoprotein (AAG), an acute phase reactant, and binds in a concentration-dependent (saturable) manner. The unbound fraction is reduced in the presence of elevated concentrations of AAG, as are found in acute myocardial infarction and in some chronic haemodialysis patients and renal transplant recipients. Free disopyramide concentrations are low relative to total concentration in these patients. Because the pharmacological effects of disopyramide are determined by unbound drug, changes in the unbound fraction could make total disopyramide concentrations misleading as a guide to therapy. Changes in protein binding do not, however, alter free disopyramide or metabolite concentrations, both of which are dependent only on dosage and intrinsic clearance. Free drug concentration measurement could potentially improve therapeutic monitoring, but is as yet of unproven clinical value. Disopyramide is cleared more rapidly in children than in adults, and therefore children require higher dosages to attain therapeutic concentrations.

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Protein Binding of Disopyramide and Elevated Alpha-1-Acid Glycoprotein Concentrations in Serum Obtained from Dialysis Patients and Renal Transplant Recipients

Cited by 39 publications

References 11 publications

The effect of chronic renal failure on drug metabolism and transport

The effect of chronic renal failure on drug metabolism and transport

Relationship between alpha 1‐acid glycoprotein and distribution of disopyramide and mono‐N‐dealkyldisopyramide in whole blood.

Clinical Pharmacokinetics of Disopyramide

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