Losartan grapefruit
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Impact of Grapefruit Juice on Losartan Pharmacokinetics
Introduction to Losartan and Grapefruit Juice Interaction
Losartan, an angiotensin II antagonist, is commonly prescribed for managing hypertension. It is metabolized into its active form, E3174, primarily by the cytochrome P450 enzymes CYP3A4 and CYP2C9. Grapefruit juice (GJ) is known to interact with various medications by inhibiting CYP3A4, potentially altering drug metabolism and efficacy.
Grapefruit Juice Inhibition of CYP3A4
Grapefruit juice is a potent inhibitor of the CYP3A4 enzyme, which plays a crucial role in the metabolism of many drugs, including losartan. When GJ is consumed, it can inhibit the intestinal phase-I metabolism of losartan, leading to changes in the drug's pharmacokinetics. A study involving healthy volunteers demonstrated that co-administration of GJ with losartan significantly increased the lag time (time to drug appearance in serum) of losartan. This indicates a delay in the drug's absorption into the bloodstream.
Altered Pharmacokinetics of Losartan and E3174
The same study found that the mean residence time (MRT) and half-life (t1/2) of the active metabolite E3174 were significantly prolonged when losartan was taken with GJ. Additionally, the area under the concentration-time curve (AUC) of E3174 was notably reduced. These changes suggest that GJ not only delays the absorption of losartan but also affects the overall exposure to its active metabolite.
P-Glycoprotein Activation by Grapefruit Juice
Grapefruit juice also activates P-glycoprotein (P-gp), a drug transporter that can influence drug absorption and efflux. Research has shown that GJ increases the net efflux of drugs that are substrates of both CYP3A4 and P-gp, including losartan. This activation of P-gp can counteract the inhibitory effects of GJ on CYP3A4, leading to a complex interaction where the overall impact on drug bioavailability can be variable and drug-specific.
Conclusion
The interaction between grapefruit juice and losartan is multifaceted, involving both inhibition of CYP3A4 and activation of P-glycoprotein. These mechanisms result in delayed absorption and altered pharmacokinetics of losartan and its active metabolite E3174. Patients taking losartan should be cautious about consuming grapefruit juice, as it can significantly impact the drug's effectiveness and safety profile.
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