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Immediate‐ versus controlled‐release disopyramide: Importance of saturable binding
Author(s) -
Davies Richard F,
Siddoway Lyle A,
Shaw Leslie,
Barbey J Toby,
Roden Dan M,
Woosley Raymond L
Publication year - 1993
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1993.103
Subject(s) - disopyramide , pharmacokinetics , chemistry , pharmacology , steady state (chemistry) , half life , blood sampling , plasma concentration , medicine
Objective : To examine the effects of saturable plasma binding on the pharmacokinetics of immediate‐release (IR) and controlled‐release (CR) disopyramide. Background : Saturable binding causes a lack of correspondence between the pharmacokinetics of total and unbound plasma disopyramide. Levels of total drug may therefore be insensitive to important differences between formulations. Methods : Patients receiving long‐term disopyramide underwent serial blood sampling during withdrawal of equivalent doses of IR and CR disopyramide, and during accumulation of IR disopyramide. Plasma disopyramide was measured by enzyme‐multiplied immunoassay technique, protein binding by ultrafiltration, and α 1 ‐acid glycoprotein by radial immunodifrusion. Pharmacologic effect was assessed by use of high‐speed ECGs. Values for plasma area under the concentration‐time curve and elimination half‐life were determined from the log‐plasma concentration data; rate of plasma drug accumulation was determined by nonlinear modeling. Results : Saturable plasma binding was evident in all patients. Comparison of total to unbound drug showed that peak‐to‐trough ratios during steady state were smaller (1.45 versus 2.39; p < 0.001), elimination half‐life was longer (12.1 versus 4.5 hours; p < 0.001), and the time to achieve 50% of steady‐state levels during drug accumulation was shorter (8.1 versus 4.3 hours; p < 0.05). Comparison of IR and CR disopyramide showed that unbound drug levels for CR disopyramide revealed lower peak plasma concentrations (0.75 versus 0.96 µg/ml) and peak‐to‐trough ratios (1.83 versus 2.31; p < 0.001). Trough plasma concentrations were similar. Fluctuations in ECG intervals during usual dosing were observed only with IR disopyramide. Conclusions : Because of saturable plasma binding, total plasma concentrations underestimate fluctuations in unbound disopyramide during usual dosing and are insensitive to significant differences between IR and CR formulations. CR disopyramide provides less interdose variation in free drug levels and more constant pharmacologic effects. Clinical Pharmacology and Therapeutics (1993) 54, 16–22; doi: 10.1038/clpt.1993.103