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Triazolam Kinetics: Interaction with Cimetidine, Propranolol, and the Combination
Author(s) -
Friedman H.,
Greenblatt David J.,
Burstein Ethan S.,
Scavone Joseph M.,
Harmatz Jerold S.,
Shader Richard I.
Publication year - 1988
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1988.tb03137.x
Subject(s) - triazolam , cimetidine , propranolol , chemistry , volunteer , pharmacology , anesthesia , medicine , benzodiazepine , receptor , biochemistry , agronomy , biology
Nineteen healthy volunteers received a single 0.5‐mg oral dose of triazolam on four occasions under the following conditions: (1) triazolam alone; (2) triazolam with Cimetidine, 300 mg four times daily; (3) triazolam with propranolol, 40 mg four times daily; (4) triazolam with both Cimetidine and propranolol. Triazolam kinetics were determined from multiple plasma concentrations measured during 24 hours after each dose. Compared with control, peak plasma triazolam concentration (C max ) was significantly increased by Cimetidine (5.4 versus 3.9 ng/mL), total area under the plasma concentration curve (AUC) increased (21.3 versus 16.1 ng/mL × hr), and oral clearance decreased (485 versus 668 mL/min). However triazolam half‐life was not increased. During propranolol alone, triazolam C max (4.1 ng/mL), AUC (14.3 ng/mL × hr), and clearance (759 mL/min) did not differ significantly from control, whereas kinetic variables for triazolam with Cimetidine plus propranolol were similar to those with Cimetidine alone. Plasma free fraction for triazolam (17 to 18% unbound) did not differ significantly among the four treatment conditions. Mean steady‐state plasma Cimetidine concentrations during trials 2 and 4 were similar (1.04 versus .98 μg/mL), whereas plasma propranolol was significantly higher during Cimetidine plus propranolol than with propranolol alone (47 versus 29 ng/ml, P < .001). Thus Cimetidine coadministration significantly inhibits triazolam clearance, causing increased triazolam AUC and C max , but without a prolongation in half‐life. Propranolol itself does not impair triazolam clearance, nor does propranolol potentiate the inhibitory effect of Cimetidine alone.