The pharmacokinetics and pharmacodynamics of diltiazem and its metabolites in healthy adults after a single oral dose
1989; Wiley; Volume: 46; Issue: 4 Linguagem: Inglês
10.1038/clpt.1989.159
ISSN1532-6535
AutoresRebecca A. Boyd, Shu Chin, Oluta Don-Pedro, Davide Verotta, Lewis B. Sheiner, Roger Williams, Kathleen M. Giacomini,
Tópico(s)Epilepsy research and treatment
ResumoClinical Pharmacology & TherapeuticsVolume 46, Issue 4 p. 408-419 Original Article The pharmacokinetics and pharmacodynamics of diltiazem and its metabolites in healthy adults after a single oral dose Rebecca A Boyd PhD, Rebecca A Boyd PhD Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorShu K Chin BS, Shu K Chin BS Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorOluta Don-Pedro BA, Oluta Don-Pedro BA Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorDavide Verotta BS, Davide Verotta BS Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorLewis B Sheiner MD, Lewis B Sheiner MD Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorRoger L Williams MD, Roger L Williams MD Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorKathleen M Giacomini PhD, Corresponding Author Kathleen M Giacomini PhD Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoKathleen M Giacomini PhD, S-926, School of Pharmacy, University of California, San Francisco, CA 94143.Search for more papers by this author Rebecca A Boyd PhD, Rebecca A Boyd PhD Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorShu K Chin BS, Shu K Chin BS Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorOluta Don-Pedro BA, Oluta Don-Pedro BA Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorDavide Verotta BS, Davide Verotta BS Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorLewis B Sheiner MD, Lewis B Sheiner MD Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorRoger L Williams MD, Roger L Williams MD Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoSearch for more papers by this authorKathleen M Giacomini PhD, Corresponding Author Kathleen M Giacomini PhD Department of Pharmacy, School of Pharmacy Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of California, San FranciscoKathleen M Giacomini PhD, S-926, School of Pharmacy, University of California, San Francisco, CA 94143.Search for more papers by this author First published: October 1989 https://doi.org/10.1038/clpt.1989.159Citations: 10AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract A potential complicating factor in the characterization of the pharmacokinetics and pharmacodynamics of diltiazem after an oral dose is the presence of two metabolites, N-demethyldiltiazem and desacetyldiltiazem, in plasma. Both N-demethyldiltiazem and desacetyldiltiazem have been shown to have pharmacologic activity in animal tissues. It is therefore possible that these metabolites contribute to the pharmacologic effect of diltiazem, but this possibility has not been explored. The purpose of this study was to investigate the pharmacokinetics and pharmacodynamics of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem. Particular attention was paid to the effect of diltiazem on atrioventricular conduction. Six healthy men received a 120 mg oral dose of diltiazem. Concentrations of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem in plasma and urine were measured by a sensitive HPLC method. Measures of pharmacologic response (heart rate, blood pressure, and PR interval) were obtained at each blood sampling time. Mean (± SD) peak plasma concentrations of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem were 174.3 ± 72.7, 42.6 ± 10.0, and 14.9 ± 3.3 ng/ml, respectively. The apparent half-lives of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem were 6.5 ± 1.4 hours, 9.4 ± 2.2 hours, and 18 ± 6.2 hours, respectively. Both N-demethyldiltiazem and diltiazem were eliminated by net renal secretion, whereas the renal clearance of desacetyldiltiazem did not exceed clearance by filtration. Both N-demethyldiltiazem and desacetyldiltiazem are bound to plasma proteins, with unbound fractions of 0.323 ± 0.035 and 0.230 ± 0.021. These values are similar to the unbound fraction of diltiazem (0.254 ± 0.027). No significant effect of diltiazem on blood pressure or heart rate was noted. However, a prolongation of the PR interval was observed in all six subjects. Furthermore, an apparent clockwise hysteresis in the concentration-effect relationship was found in four of the six subjects. These findings suggest that some form of acute tolerance to the electrophysiologic effect of diltiazem develops, but the results of pharmacodynamic modeling suggest that this is not caused by the antagonistic effects the metabolites. Clinical Pharmacology and Therapeutics (1989) 46, 408–419; doi:10.1038/clpt.1989.159 Citing Literature Volume46, Issue4October 1989Pages 408-419 RelatedInformation
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