{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:26:01Z","timestamp":1790987161252,"version":"4.1.0"},"reference-count":0,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2001,5,2]],"date-time":"2001-05-02T00:00:00Z","timestamp":988761600000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2001,5]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Racemic (<jats:italic>R<\/jats:italic>\/<jats:italic>S)\u2010<\/jats:italic>verapamil is widely used in the management of chronic atrial fibrillation. The negative dromotropic effect is mainly mediated by the <jats:italic>S<\/jats:italic>\u2010enantiomer, which is preferentially metabolized. Previous studies report an accumulation of <jats:italic>R<\/jats:italic>\/<jats:italic>S\u2010<\/jats:italic>verapamil during long\u2010term oral treatment of patients with chronic atrial fibrillation. However, the specific disposition of <jats:italic>S<\/jats:italic>\u2010verapamil and the pharmacologic effects were not assessed. Therefore uncertainties about the need for dose adjustments remain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using stable isotope technology and a stereospecific assay, we compared the pharmacokinetics and pharmacodynamics of intravenous (10 mg of d<jats:sub>7<\/jats:sub>\u2010<jats:italic>R<\/jats:italic>\/<jats:italic>S<\/jats:italic>\u2010verapamil) and oral (240 mg of slow release (SR) d<jats:sub>0<\/jats:sub>\u2010<jats:italic>R<\/jats:italic>\/<jats:italic>S<\/jats:italic>\u2010verapamil) <jats:italic>R<\/jats:italic>\u2013verapamil and <jats:italic>S<\/jats:italic>\u2010verapamil after the first dose (day 1) and after 3 weeks (day 21) of continuous oral therapy in 8 patients with long\u2010term atrial fibrillation. On both study days, serum samples were obtained for the analysis of d<jats:sub>7<\/jats:sub>\u2010 and d<jats:sub>0<\/jats:sub>\u2010<jats:italic>R<\/jats:italic>\u2010verapamil and <jats:italic>S<\/jats:italic>\u2010verapamil. Heart rate (HR) was monitored with electrocardiography (with each blood sample) and Holter electrocardiography (before the study, on day 1, and on day 21).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with day 1, clearance of oral <jats:italic>R<\/jats:italic>\u2010verapamil and <jats:italic>S<\/jats:italic>\u2010verapamil was significantly reduced on day 21 (1007 \u00b1 380 versus 651 \u00b1 253 mL\/min [\u201335%] and 5481 \u00b1 2731 versus 2855 \u00b1 1097 mL\/min [\u201348%], respectively; <jats:italic>P<\/jats:italic> &lt; .05), whereas only a moderate decrease was observed for intravenous <jats:italic>R<\/jats:italic>\u2010verapamil and <jats:italic>S<\/jats:italic>\u2010verapamil (\u201323% and \u221214%, respectively, not significant). Mean HR (89 \u00b1 11 bpm before verapamil) was effectively reduced, with the same effects on day 1 (68 \u00b1 8 bpm) and day 21 (68 \u00b1 8 bpm). Compared with day 1, the HR reduction per ng\/mL of <jats:italic>S<\/jats:italic>\u2010verapamil (calculated by the area under the curve [from 0\u201324 hours] ratio of HR reduction and <jats:italic>S<\/jats:italic>\u2010verapamil concentration) was significantly lower on day 21 (0.7 \u00b1 0.4 versus 1.2 \u00b1 0.7 [bpm] \u00b7 [ng\/mL]<jats:sup>\u22121<\/jats:sup>, for day 21 versus day 1; <jats:italic>P<\/jats:italic> &lt; .01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In patients with chronic atrial fibrillation, clearance of oral, but not intravenous, <jats:italic>S<\/jats:italic>\u2010verapamil and <jats:italic>R<\/jats:italic>\u2010verapamil 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 <jats:italic>S<\/jats:italic>\u2010verapamil observed with regular dosing. The data suggest that despite accumulation of the drug individual verapamil doses can be maintained during long\u2010term oral rate control therapy.<\/jats:p><jats:p><jats:italic>Clinical Pharmacology &amp; Therapeutics<\/jats:italic> (2001) <jats:bold>69<\/jats:bold>, 324\u2013332; doi: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1067\/mcp.2001.115125\">10.1067\/mcp.2001.115125<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1067\/mcp.2001.115125","type":"journal-article","created":{"date-parts":[[2002,7,25]],"date-time":"2002-07-25T04:21:43Z","timestamp":1027570903000},"page":"324-332","source":"Crossref","is-referenced-by-count":9,"title":["Disposition and pharmacologic effects of <i>R<\/i>\/<i>S<\/i>\u2010verapamil in patients with chronic atrial fibrillation: An investigation comparing single and multiple dosing"],"prefix":"10.1111","volume":"69","author":[{"given":"Dagmar","family":"Busse","sequence":"first","affiliation":[{"name":"Dr Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology Division of Clinical Pharmacology and the Department of Internal Medicine III Eberhard Karl's University, Stuttgart and T\u00fcbingen  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin F.","family":"Fromm","sequence":"additional","affiliation":[{"name":"Dr Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology Division of Clinical Pharmacology and the Department of Internal Medicine III Eberhard Karl's University, Stuttgart and T\u00fcbingen  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"M\u00f6rike","sequence":"additional","affiliation":[{"name":"Dr Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology Division of Clinical Pharmacology and the Department of Internal Medicine III Eberhard Karl's University, Stuttgart and T\u00fcbingen  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siegfried","family":"Drescher","sequence":"additional","affiliation":[{"name":"Dr Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology Division of Clinical Pharmacology and the Department of Internal Medicine III Eberhard Karl's University, Stuttgart and T\u00fcbingen  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"K\u00fchlkamp","sequence":"additional","affiliation":[{"name":"Dr Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology Division of Clinical Pharmacology and the Department of Internal Medicine III Eberhard Karl's University, Stuttgart and T\u00fcbingen  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Eichelbaum","sequence":"additional","affiliation":[{"name":"Dr Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology Division of Clinical Pharmacology and the Department of Internal Medicine III Eberhard Karl's University, Stuttgart and T\u00fcbingen  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2001,5,2]]},"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1067\/mcp.2001.115125","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,19]],"date-time":"2023-11-19T15:04:37Z","timestamp":1700406277000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1067\/mcp.2001.115125"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,5]]},"references-count":0,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2001,5]]}},"alternative-id":["10.1067\/mcp.2001.115125"],"URL":"https:\/\/doi.org\/10.1067\/mcp.2001.115125","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,5]]}}}