Bioavailability of total and unbound disopyramide: implications for clinical use of the immediate and controlled-release dosage forms

• Published in: Journal of clinical pharmacology Vol. 34; no. 8; p. 823
• Main Authors: Piscitelli, D A, Fischer, J H, Schoen, M D, Hoon, T J, Bauman, J L
• Format: Journal Article
• Language: English
• Published: England 01.08.1994
• Subjects: Adolescent; Adult; Biological Availability; Delayed-Action Preparations; Disopyramide - administration & dosage; Disopyramide - pharmacokinetics; Disopyramide - pharmacology; Humans; Male; Protein Binding
• ISSN: 0091-2700
• DOI: 10.1002/j.1552-4604.1994.tb02046.x

This study further characterized the impact of concentration-dependent protein binding on the bioavailability and clinical use of the immediate-release (IR) and controlled-release (CR) dosage forms of disopyramide after single doses and during steady-state conditions in ten healthy volunteers. Consistent with the clinical use of these products, steady state has incorporated an IR to CR conversion step. Side effects and electrocardiographic actions were quantitated using a visual analog scale and serial Holter monitor recordings, respectively. Significant decreases resulted in area under the curve for total disopyramide between single dose and steady state: IR, 47.8 +/- 13.6 versus 33.0 +/- 6.4 mg/Lxh (P < .05); and CR, 46.9 +/- 9.5 versus 31.7 +/- 5.9 mg/Lxh (P < .05). In contrast, there were no differences in area under the curve for unbound disopyramide between phases or products. During conversion, the mean IR peak significantly decreased (P < .05) to the nadir before the first CR dose for total (37%) and unbound (60%) concentrations. There were no major differences in change in QT interval or side effects detected between products or phases. These findings indicate that, because of concentration-dependent protein binding, unbound, not total, concentrations should be used to estimate the bioavailability of disopyramide. Also, although the previously recommended conversion method (first CR dose 6 hours after the last IR dose) should provide an adequate transition in most, an alternative method (combined first CR with last IR dose) is indicated in select patients.