 |
 |
 |
 |
 |
 |
 |
|
|
|
|||||||||
|
|||||||||||
Distinguished University Professor of Pharmacology, Department of Pharmacology, College of Pharmacy, University of Toledo, Toledo, OH
Pharmacotherapy Specialist, Lexi-Comp, Inc., Hudson, OH
Reprints: Dr. Bachmann, Department of Pharmacology, College of Pharmacy, University of Toledo, 2801 W. Bancroft St., Toledo, OH 43606-3390, fax 419/530-1909, Kbachma{at}utnet.utoledo.edu
OBJECTIVE: To review the use of inhibitory constants (Ki) determined from in vitro experiments in the prediction of the significance of inhibitory drug-drug interactions (DDIs).
DATA SOURCES: Searches of MEDLINE (1966-August 2004) and manual review of journals, conference proceedings, reference textbooks, and Web sites were performed using the key search terms cytochrome P450, drug-drug interaction, inhibition constant, and Ki.
STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated, and information deemed relevant was included for this review.
DATA SYNTHESIS: The cytochrome P450 isoenzymes factor prominently in the explanation of numerous DDIs. Although the regulation of these enzymes by one drug can affect the pharmacokinetics of other drugs, the consequences may not necessarily be significant either in terms of pharmacokinetic or clinical outcomes. Yet, many DDI monographs originate as unconfirmed case reports that implicate the influence of one drug on the CYP-mediated metabolism of another, and these often uncorroborated mechanisms can eventually become regarded as dogma. One consequence of this process is the overprediction of potentially important DDIs. The pharmaceutical industry, Food and Drug Administration, and pharmaceutical scientists have developed a strategy for predicting the significance of inhibitory DDIs at the earliest possible stages of drug development based on a new chemical entity's Ki value, determined in vitro.
CONCLUSIONS: We suggest that the use of Ki values of drugs purported to behave as CYP inhibitors be incorporated in the assessment of case reports that ascribe DDIs to inhibition of metabolism of one drug by another.
Key Words: cytochrome P450, drug-drug interactions, inhibition, inhibition constant
Published Online, May 10, 2005. www.theannals.com, DOI 10.1345/aph.1E508
This article has been cited by other articles:
|
|
 |
|
  O. A. Fahmi, S. Hurst, D. Plowchalk, J. Cook, F. Guo, K. Youdim, M. Dickins, A. Phipps, A. Darekar, R. Hyland, et al. Comparison of Different Algorithms for Predicting Clinical Drug-Drug Interactions, Based on the Use of CYP3A4 in Vitro Data: Predictions of Compounds as Precipitants of Interaction Drug Metab. Dispos., August 1, 2009; 37(8): 1658 - 1666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Rock, R. S. Foti, and J. T. Pearson The Combination of Chemical and Antibody Inhibitors for Superior P450 3A Inhibition in Reaction Phenotyping Studies Drug Metab. Dispos., December 1, 2008; 36(12): 2410 - 2413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Nakashima, H. Takama, Y. Ogasawara, T. Kawakami, T. Nishitoba, S. Hoshi, E. Uchida, and H. Tanaka Effect of Cinacalcet Hydrochloride, a New Calcimimetic Agent, on the Pharmacokinetics of Dextromethorphan: In Vitro and Clinical Studies J. Clin. Pharmacol., October 1, 2007; 47(10): 1311 - 1319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Watanabe, K. Nakamura, N. Okudaira, O. Okazaki, and K.-i. Sudo Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process Drug Metab. Dispos., July 1, 2007; 35(7): 1232 - 1238. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
 |
 |
 |
 |
