Interplay between CYP3A and drug transporters

Abstract

Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp/MDR1) are two important detoxifying systems that protect us against many potentially harmful xenobiotics but their activity also strongly limits the absorption of a wide variety of drugs. Both CYP3A and P-gp have a very broad substrate spectrum and it is noteworthy that there is a large overlap between their substrates. In view of this, it has been hypothesized that it is the combined (intestinal) activity of CYP3A and P-gp that makes for efficient first-pass metabolism of many orally administered drugs. P-gp may reduce the probability of CYP3A4 saturation and would also give the enzyme repeated access to its substrates. However, little in vivo evidence for functional synergy between CYP3A and P-gp is currently available. By generating and utilizing novel mouse models we aimed to obtain more insight into the importance of intestinal CYP3A-dependent metabolism and the functional interplay between CYP3A and P-gp. The studies described in this thesis demonstrate the value of knockout and transgenic mouse models to investigate the individual and combined impact of CYP3A and drug transporters such as P-gp on the pharmacokinetics of drugs. For example, the importance of intestinal metabolism has long been a matter of debate but our studies with tissue-specific CYP3A4 transgenic mice have provided unequivocal evidence that the impact of intestinal CYP3A4-dependent metabolism can even surpass that of hepatic metabolism after oral drug administration. The generation of Cyp3a/P-gp-/- mice has provided a novel in vivo tool to get more insight into how CYP3A and P-gp may work together. We demonstrated that the combined absence of both CYP3A and P-gp can result in a dramatic, disproportionate increase in drug exposure with a concomitantly increased (and possibly qualitatively altered) risk of toxicity. Especially with drugs that have a narrow therapeutic window, there are serious risks when such drugs are deliberately or unintentionally co-administered with other drugs or food constituents that interfere with CYP3A and P-gp activity. The risk of such drug-drug and drug-food interactions is especially relevant given the high number and large overlap in substrates and inhibitors for CYP3A and P-gp. Variable activity of CYP3A alone can lead to lethal overdosing or subtherapeutic underdosing of orally taken drugs. It is clear from the work in this thesis that interfering with both CYP3A and P-gp activity could drastically exacerbate such consequences, and should therefore be considered with caution during further drug development and application.