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Disposition and pharmacologic effects of R/S-verapamil in patients with chronic atrial fibrillation: an investigation comparing single and multiple dosing.

AbstractBACKGROUND:
Racemic (R /S)- verapamil is widely used in the management of chronic atrial fibrillation. The negative dromotropic effect is mainly mediated by the S -enantiomer, which is preferentially metabolized. Previous studies report an accumulation of R /S- verapamil during long-term oral treatment of patients with chronic atrial fibrillation. However, the specific disposition of S -verapamil and the pharmacologic effects were not assessed. Therefore uncertainties about the need for dose adjustments remain.
METHODS:
Using stable isotope technology and a stereospecific assay, we compared the pharmacokinetics and pharmacodynamics of intravenous (10 mg of d(7)-R /S -verapamil) and oral (240 mg of slow release (SR) d(0)-R /S -verapamil) R -verapamil and S -verapamil after the first dose (day 1) and after 3 weeks (day 21) of continuous oral therapy in 8 patients with long-term atrial fibrillation. On both study days, serum samples were obtained for the analysis of d(7)- and d(0)-R -verapamil and S -verapamil. Heart rate (HR) was monitored with electrocardiography (with each blood sample) and Holter electrocardiography (before the study, on day 1, and on day 21).
RESULTS:
Compared with day 1, clearance of oral R -verapamil and S -verapamil was significantly reduced on day 21 (1007 +/- 380 versus 651 +/- 253 mL/min [-35%] and 5481 +/- 2731 versus 2855 +/- 1097 mL/min [-48%], respectively; P <.05), whereas only a moderate decrease was observed for intravenous R -verapamil and S -verapamil (-23% and -14%, respectively, not significant). Mean HR (89 +/- 11 bpm before verapamil) was effectively reduced, with the same effects on day 1 (68 +/- 8 bpm) and day 21 (68 +/- 8 bpm). Compared with day 1, the HR reduction per ng/mL of S -verapamil (calculated by the area under the curve [from 0-24 hours] ratio of HR reduction and S -verapamil concentration) was significantly lower on day 21 (0.7 +/- 0.4 versus 1.2 +/- 0.7 [bpm]. [ng/mL](-1), for day 21 versus day 1; P <.01).
CONCLUSIONS:
In patients with chronic atrial fibrillation, clearance of oral, but not intravenous, S -verapamil and R -verapamil is significantly reduced with multiple doses compared with a single dose, thereby indicating predominant impairment of prehepatic rather than hepatic metabolism as the underlying mechanism. However, this kinetic change is clinically compensated by a decrease in the responsiveness to S -verapamil observed with regular dosing. The data suggest that despite accumulation of the drug individual verapamil doses can be maintained during long-term oral rate control therapy.
AuthorsD Busse, M F Fromm, K Mörike, S Drescher, V Kühlkamp, M Eichelbaum
JournalClinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 69 Issue 5 Pg. 324-32 (May 2001) ISSN: 0009-9236 [Print] United States
PMID11372000 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Calcium Channel Blockers
  • Disaccharides
  • Glucuronates
  • O-(glucuronic acid 2-sulfate)-(1--4)-O-(2,5)-anhydromannitol 6-sulfate
  • Verapamil
Topics
  • Administration, Oral
  • Aged
  • Area Under Curve
  • Atrial Fibrillation (drug therapy, metabolism)
  • Blood Pressure (drug effects)
  • Calcium Channel Blockers (administration & dosage, pharmacokinetics, therapeutic use)
  • Chromatography, High Pressure Liquid
  • Chronic Disease
  • Disaccharides
  • Dose-Response Relationship, Drug
  • Electrocardiography, Ambulatory
  • Exercise Test
  • Female
  • Glucuronates
  • Half-Life
  • Humans
  • Injections, Intravenous
  • Male
  • Metabolic Clearance Rate
  • Stereoisomerism
  • Tissue Distribution
  • Verapamil (administration & dosage, pharmacokinetics, therapeutic use)

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