Mice predict the effectiveness of orally taken drugs

The amount of an orally taken drug that makes it to the site in the body at which it exerts its effects is much lower than the amount of an intravenously administered drug and it varies considerably between individuals. One reason for this is that a substantial proportion of more than half of all orally prescribed medications are broken down in the intestine and liver, by an enzyme known as CYP3A, before reaching their site of action (a process known as first-pass metabolism). In a new study, Alfred Schinkel and colleagues from The Netherlands Cancer Institute, have developed a new mouse model for predicting the loss in available drug due to metabolism by CYP3A.

In the study, mice lacking all 8 genes encoding functional mouse CYP3A proteins (Cyp3A-/- mice) were generated and the anticancer chemotherapeutic agent docetaxol was found to accumulate in the tissues of these mice at much higher levels than in normal mice. Engineering Cyp3A-/- mice to express human CYP3A in the intestine dramatically decreased the absorption of orally administered docetaxol into the blood. By contrast, Cyp3A-/- mice engineered to express human CYP3A in the liver showed only a slight decrease in the amount of orally administered docetaxol reaching the blood. These data indicate a key role for CYP3A in the intestine as a mediator of first-pass metabolism and led the authors to suggest that these mice provide a powerful tool to help predict whether drugs being developed will work effectively if given orally. In an accompanying commentary Kenneth Thummel from the University of Washington, Seattle, expands on the usefulness of these mice as tools for drug development and discusses how these data might explain interpatient variability in first-pass metabolism.

TITLE: New models for understanding the role of cytochrome P450 3A in xenobiotic metabolism

AUTHOR CONTACT: Alfred H. Schinkel
The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Phone: 31-20-5122046; Fax: 31-20-5122050; E-mail: a.schinkel@nki.nl.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33435

ACCOMPANYING COMMENTARY

TITLE: Gut instincts: CYP3A4 and intestinal drug metabolism

AUTHOR CONTACT: Kenneth E. Thummel
University of Washington, Seattle, Washington, USA.
Phone: (206) 543-0819; Fax: (206) 543-3204; Email: Thummel@u.washington.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34007