Influence of Acetaminophen on Pharmacokinetics and Pharmacodynamics of Midazolam in Healthy Volunteers


Background: Midazolam and acetaminophen are often co-administered in anesthesia practice. Both are metabolized by CYP 3A4 enzyme in the liver, and hence compete for the enzyme sites. This might lead to reduced metabolic breakdown and enhanced pharmacodynamic effects of midazolam in the presence of acetaminophen. Methods: The present study was undertaken to test this hypothesis. After IRB approval from Mount Sinai Medical Center, 15 healthy volunteers were used for 2 tests. For the first test, they were randomly assigned to receive oral doses of either midazolam 0.3 mg/kg in cherry syrup (Protocol A), or midazolam 0.3 mg/kg plus cherry flavored acetaminophen 15 mg/kg (Protocol B). At set intervals from 0 to 480 min, the blood levels of midazolam and the subjects pulse rate, mean arterial pressure, respiratory rate, BIS index, and OAA/S scores were determined. After 2 weeks, the same subjects underwent the second test; they received the other medication protocol. Results: Acetaminophen slightly, but not significantly, increased the half life of blood midazolam, and the depressive effects of midazolam on the clinical signs of the subjects. Conclusion: These results lead us to conclude that there is no need to reduce the doses of midazolam when used in combination with acetaminophen.

Share and Cite:

Feierman, D. , Suresh, T. , Pagala, M. and Silverstein, J. (2015) Influence of Acetaminophen on Pharmacokinetics and Pharmacodynamics of Midazolam in Healthy Volunteers. Open Journal of Anesthesiology, 5, 116-121. doi: 10.4236/ojanes.2015.56022.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Gorski, J.C., Jones, D.R., Haehner-Daniels, B.D., Hamman, M.A., O’Mara Jr., E.M. and Hall, S.D. (1998) The Contribution of Intestinal and Hepatic CYP3A to the Interaction between Midazolam and Clarithromycin. Clinical Pharmacology and Therapeutics, 64, 133-143.
[2] Kronbach, T., Mathys, D., Umeno, M., Gonzalez, F.J. and Meyer, U.A. (1989) Oxidation of Midazolam and Triazolam by Human Liver Cytochrome P450IIIA4. Molecular Pharmacology, 36, 89-96.
[3] Kostrubsky, V.E., Szakacs, J.G., Jeffery, E.H., Wood, S.G., Bement, W.J., Wrighton, S.A., Sinclair, P.R. and Sinclair, J.F. (1997) Role of CYP3A in Ethanol-Mediated Increases in Acetaminophen Hepatotoxicity. Toxicology and Applied Pharmacology, 143, 315-323.
[4] Feierman, D.E. (2000) The Effect of Paracetamol (Acetaminophen) on Fentanyl Metabolism in Vitro. Acta Anaesthesiologica Scandinavica, 44, 560-563.

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.