Advertisement

Do Cytochrome P450 Effects Predict Drug Interactions in Real Life?

Summary and Comment |
June 17, 2014

Do Cytochrome P450 Effects Predict Drug Interactions in Real Life?

  1. Steven Dubovsky, MD

As seen in this study of fluoxetine, drug metabolism is much more complex than a single effect on a single cytochrome P450 enzyme.

  1. Steven Dubovsky, MD

Fluoxetine is known as both a substrate and inhibitor of cytochrome P (CYP) 450 2D6, leading to attempts to predict its actions in patients with different 2D6 genotypes and its interactions with other 2D6 substrates. Researchers examined whether knowing about this enzyme is sufficient to predict clinical interactions.

In vitro, both fluoxetine and its major active metabolite, norfluoxetine, were strong inhibitors of 2D6, 2C19, and 3A4. In vivo, 12 to 14 days of fluoxetine administration in 10 normal subjects significantly reduced clearance of the 2D6 substrate dextromethorphan and the 2C19 substrate omeprazole (but did not alter its elimination half-life). Clearance and half-life of the 3A4 substrate midazolam were unchanged, because fluoxetine and its metabolite also induced messenger RNA of 3A4 at the same time that it inhibited the actual enzyme. Stereoisomers of the parent drug and its metabolite had different actions on CYP450 enzymes.

Comment

The current models for predicting CYP450 interactions of common psychiatric drugs are based primarily on known effects on a single enzyme, or when more than one action is expected, they are assumed to occur in just one direction. This study shows that it is necessary to account for all possible enzyme effects of a medication, including enzymes that are affected in different directions and the divergent effects of a drug and its stereoisomers and metabolites. When effects on drug transport proteins are factored in, predicting the metabolism and interactions of various drugs becomes more complex. The clinical take-home: Clinicians should observe patients closely after starting any medication rather than merely relying on published actions or those predicted by commercial genotyping.

  • Disclosures for Steven Dubovsky, MD at time of publication Grant / Research support Otsuka; Tower Foundation; Research for Health, Hoffman-La Roche; Pfizer; Takeda Editorial boards Mind and Brain; Bulletin of the Menninger Clinic; Current Psychiatry; Journal of Psychosomatic Research

Citation(s):

Your Comment

(will not be published)

Filtered HTML

  • Allowed HTML tags: <a> <em> <strong> <cite> <blockquote> <code> <ul> <ol> <li> <dl> <dt> <dd>
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Do you have any conflict of interest to disclose?
CAPTCHA
This question is for testing whether you are a human visitor and to prevent automated spam submissions.
Image CAPTCHA
Enter the characters shown in the image.

Vertical Tabs

* Required

Reader comments are intended to encourage lively discussion of clinical topics with your peers in the medical community. We ask that you keep your remarks to a reasonable length, and we reserve the right to withhold publication of remarks that do not meet this standard.

PRIVACY: We will not use your email address, submitted for a comment, for any other purpose nor sell, rent, or share your e-mail address with any third parties. Please see our Privacy Policy.

Advertisement
Advertisement
Advertisement