Disposition and pharmacologic effects of R/S-verapamil in patients with chronic atrial fibrillation: an investigation comparing single and multiple dosing.
BACKGROUND
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.
Busse
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Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, and the Division of Clinical Pharmacology and the Department of Internal Medicine III, Eberhard Karl's University, Germany. dagmar.busse@ikp-stuttgart.de
Fromm
M F
MF
Mörike
K
K
Drescher
S
S
Kühlkamp
V
V
Eichelbaum
M
M
D000284:Administration, Oral; D000368:Aged; D019540:Area Under Curve; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D002908:Chronic Disease; D004187:Disaccharides; D004305:Dose-Response Relationship, Drug; D015716:Electrocardiography, Ambulatory; D005080:Exercise Test; D005260:Female; D005965:Glucuronates; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D013237:Stereoisomerism; D014018:Tissue Distribution; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D002121:Calcium Channel Blockers; D004187:Disaccharides; D005965:Glucuronates; C059554:O-(glucuronic acid 2-sulfate)-(1--4)-O-(2,5)-anhydromannitol 6-sulfate; D014700:Verapamil