The Open Drug Metabolism Journal


ISSN: 1874-0731 ― Volume 5, 2011

Pharmacokinetics and Hemodynamic Effects of Diltiazem in Rats Following Single vs Multiple Doses In Vivo#

Pollen K. Yeung*, Angelia Alcos, Jinglan Tang
Pharmacokinetics and Metabolism Laboratory, College of Pharmacy & Department of Medicine, Faculties of Health Professions and Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 3J5, Canada


The objective of the study was to compare the pharmacokinetics and hemodynamic effects of diltiazem (DTZ) after single dose and multiple doses using an in vivo rat model. Male SD rats (n = 6 - 8 per group) weighing between 350 - 450 g were used. Each rat received either a single 20mg/kg dose of DTZ or 5mg/kg sc twice daily for 5 doses by subcutaneous (sc) injection. Plasma concentrations of DTZ and its major metabolites were determined by HPLC for up to 8 h. In addition, Systolic Blood Pressure, Diastolic Blood Pressure and Heart Rate were continuously recorded, and analysed using WinNonLin® and considered significant when p < 0.05. The results indicate that after the single 20 mg/kg subcutaneous injection, SBP fell from 138 ± 4 to 125 ± 3 mmHg (-9.4%), DBP from 105 ± 3 to 78 ± 4 mmHg (-26%), and HR from 442 ± 12 to 396 ± 7 bpm (-10%). After 5 mg/kg twice daily for 5 doses, the observed SBP was reduced from 127 ± 5 to 111 ± 7 mmHg (-13%), DBP from 108 ± 6 to 88 ± 7 mmgHg (-19%), and HR from 458 ± 11 to 407 ± 22 bpm (-11%). The pharmacokinetics and hemodynamic data were characterized by an Inhibitory Emax model, which showed a similar profile following the single and multiple doses. Multiple regression analyses of the data predicted that the metabolites in particular deacetyl diltiazem (M1) contributed significantly to the blood pressure lowering effects following multiple doses, but the effects of metabolite were minimal after single dose.

Keywords:: Diltiazem, pharmacodynamics, pharmacokinetics, metabolism, rats..

Article Information

Identifiers and Pagination:

Year: 2009
Volume: 3
First Page: 56
Last Page: 62
Publisher Id: TODMJ-3-56
DOI: 10.2174/1874073100903010056

Article History:

Received Date: 20/3/2009
Revision Received Date: 23/5/2009
Acceptance Date: 25/5/2009
Electronic publication date: 30/6/2009
Collection year: 2009

© Yeung et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http: // which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Pharmacokinetics & Metabolism Laboratory, College of Pharmacy & Department of Medicine, 5968 College Street, Burbidge Building, Dalhousie University, Halifax, Nova Scotia, B3H 3J5, Canada; Tel: (902) 494-3845; Fax: (902) 494-1396; E-mail: Pollen.Yeung@Dal.Ca# The paper was presented in part at the 107th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Baltimore, MD, USA (March 8 – 11, 2006).

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