¹Bureau of Drug Research, Drugs Directorate, Health Protection Branch, Health Canada, and Ottawa Heart Institute, Ottawa, Ontario, Canada

Correspondence: Sylvie Laganière, PhD, Biopharmaceutics and Pharmacodynamics Division, Bureau of Drug Research, 2-West, Banting Research Centre 2202C1, Tunney's Pasture, Ottawa, Ontario, K1A 0L2, Canada.

^*Supported by Health Canada, Ottawa, Ontario.

Received 5 January 1996; Accepted 17 April 1996.

Abstract

Objectives: To examine the pharmacokinetic and pharmacodynamic interactions between quinidine and diltiazem because both drugs can inhibit drug metabolism.

Methods: Twelve fasting, healthy male volunteers (age, 24 5 years; weight, 75 10 kg) received a single oral dose of diltiazem (60 mg) or quinidine (200 mg), alone and on a background of the other drug, in a crossover study. Background treatment consisted of 100 mg quinidine twice a day or 90 mg sustained-release diltiazem twice a day for 2 days before the study day.

Results: Pretreatment with diltiazem significantly (p < 0.05) increased the area under the curve of quinidine from 7414 1965 to 11,213 2610 ng hr/ml and increased its terminal elimination half-life (t_1/2) from 6.8 1.1 to 9.3 1.5 hours. Its oral clearance was decreased from 0.39 0.1 to 0.25 0.1 L/hr/kg, whereas the maximal concentration was not significantly affected. Diltiazem disposition was not significantly affected by pretreatment with quinidine. Diltiazem pretreatment increased QT_c and PR intervals and decreased heart rate and diastolic blood pressure. No significant pharmacodynamic differences were shown for diltiazem alone versus quinidine pretreatment.

Conclusion: Diltiazem significantly decreased the clearance and increased the t_1/22 of quinidine, but quinidine did not alter the kinetics of diltiazem with the dose used. No significant pharmacodynamic interaction was shown for the combination that would not be predicted from individual drug administration.