Displacement of Disopyramide from Human Plasma Proteins

Pedersen, L. E.; Bonde, Jan

doi:10.1111/bcpt.1985.57.3.223

Cited by 4 publications

(2 citation statements)

References 7 publications

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“…Tahle 3 Free fraction (YO) of lidocaine with no disopyramide added and at a concentration of disopyramide of 5.9 and 14.7 pmol/l given at 3 concentrations of lidocaine: 0.4, 12.8 and 25.6 pmol/l. Pedersen & Bonde (1985) have shown that lidocaine does not displace disopyramide significantly from a-1acid glycoprotein. The significant displacement of lidocaine by disopyramide at all serum levels of lidocaine implies a stronger binding affinity of disopyramide than lidocaine to a-1-acid glycoprotein.…”

Section: Jan Bonde Et a Lmentioning

confidence: 95%

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Displacement of Lidocaine from Human Plasma Proteins by Disopyramide

Bonde¹,

Jensen²,

Burgaard³

et al. 1987

Pharmacology & Toxicology

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Displacement from human plasma proteins of lidocaine by disopyramide was investigated in serum from nine patients receiving lidocaine treatment because of severe ventricular arrhythmias. From each patient disopyramide in concentrations of 5.9 and 14.7 mumol/l was added to three different serum concentrations of lidocaine and the displacement was examined. At a serum concentration of disopyramide of 14.7 mumol/l the percentage of unbound lidocaine increased from 30.4 +/- 0.2 to 36.3 +/- 0.2% (mean +/- S.E.M., P less than 0.001) at an average total serum concentration of lidocaine of 22.7 mumol/l. The study implies a stronger binding affinity of disopyramide than lidocaine to alpha-1-acid glycoprotein. We recommend caution when using disopyramide immediately after an infusion of lidocaine. With the dosage regimen used serum concentrations considerably above the suggested therapeutic level were achieved in the majority of patients.

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Section: Jan Bonde Et a Lmentioning

confidence: 95%

“…Pedersen & Bonde (1985) have shown that lidocaine does not displace disopyramide from a-1 -acid glycoprotein. We therefore wanted to study the reverse displacement of lidocaine from a-1-acid glycoprotein by disopyramide.…”

mentioning

confidence: 99%

Displacement of Lidocaine from Human Plasma Proteins by Disopyramide

Bonde¹,

Jensen²,

Burgaard³

et al. 1987

Pharmacology & Toxicology

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Effects of the enantiomers of disopyramide and its major metabolite on the electrophysiological characteristics of the guinea-pig papillary muscle

Vanhoutte

Vereecke

Carmeliet

et al. 1991

Naunyn-Schmiedeberg's Arch Pharmacol

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Disopyramide, a Class Ia antiarrhythmic drug, is clinically used as a racemic mixture; R(-)disopyramide and S(+)disopyramide. The major metabolite in man is desisopropyldisopyramide: R(-)desisopropyldisopyramide and S(+)desisopropyldisopyramide. The effects of the four compounds were compared on the electrophysiological characteristics of the guinea-pig papillary muscle using the standard microelectrode technique. At an external K+ concentration of 5.4 mmol/l and a stimulation frequency of 1 Hz, S(+)disopyramide (20 mumols/l) increased action potential duration (APD) by more than 18%, while it was diminished by 6% in the presence of R(-)disopyramide. Resting membrane potential amounted to -87.1 +/- 0.5 mV (n = 14) and -85.6 +/- 1.2 mV (n = 10), respectively. Also a small but significant difference in effect on the maximal rate of depolarization was observed, R(-)disopyramide being more potent, related with a slower recovery of the maximal rate of depolarization. The enantiomers of the metabolite appeared to be three times less potent than those of the parent drug in their effect on the maximal rate of depolarization. The characteristics of the enantiomers of the metabolite correlated with those of the parent drug: also the R(-)enantiomer was more potent in decreasing the maximal rate of depolarization and caused more shortening of the action potential than the S(+)enantiomer. Time constants for onset and recovery of/from rate dependent block of the maximal rate of depolarization were dependent upon the external K+ concentration, both for the enantiomers of the parent drug and those of the metabolite. Onset slowed down while recovery accelerated when external K+ was increased. Time constants were lower for the metabolite. When stimulation interval was shortened, the effect on the maximal rate of depolarisation increased. Only for the metabolite statistical significant stereoselective differences were observed at all stimulation intervals. The effects on the action potential duration were dependent upon stimulation interval; for all enantiomers the action potential duration tended to be relatively (% of control) higher at short stimulation intervals than at large stimulation intervals. The effect on the maximal rate of depolarization was also voltage dependent, but no significant differences were observed between the enantiomers, for the parent drug as well as for the metabolite.

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The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery

Smith

Kerns³

2010

Nat Rev Drug Discov

750

656

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Data from in vitro plasma protein binding experiments that determine the fraction of protein-bound drug are frequently used in drug discovery to guide structure design and to prioritize compounds for in vivo studies. However, we consider that these practices are usually misleading, because in vivo efficacy is determined by the free (unbound) drug concentration surrounding the therapeutic target, not by the free drug fraction. These practices yield no enhancement of the in vivo free drug concentration. So, decisions based on free drug fraction could result in the wrong compounds being advanced through drug discovery programmes. This Perspective provides guidance on the application of plasma protein binding information in drug discovery.

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Displacement of Disopyramide from Human Plasma Proteins

Cited by 4 publications

References 7 publications

Displacement of Lidocaine from Human Plasma Proteins by Disopyramide

Displacement of Lidocaine from Human Plasma Proteins by Disopyramide

Effects of the enantiomers of disopyramide and its major metabolite on the electrophysiological characteristics of the guinea-pig papillary muscle

The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery

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