Milk thistle (silymarin)–Losartan Pharmacokinetic Interaction
Milk thistle (silymarin) can inhibit CYP2C9, which is responsible for conversion of losartan to its major pharmacologically active metabolite E-3174. [1]
Mechanism of Interaction
- Losartan is converted to E-3174 via CYP2C9-mediated metabolism. [1]
- Silymarin can inhibit CYP2C9 activity. [1]
Expected Pharmacokinetic Effects
- Silymarin has been associated with increased losartan exposure (AUC and Cmax increases) in CYP2C91/1 wild-type homozygotes. [1]
- Silymarin has been associated with reduced oral clearance of losartan in CYP2C91/1 wild-type homozygotes. [1]
- Silymarin has been associated with decreased exposure of the active metabolite E-3174. [1]
Evidence Supporting This Interaction
- In a human pharmacokinetic study summarized in a peer-reviewed review, silymarin increased losartan AUC(0-24) by 109%, increased losartan AUC(0-∞) by 108%, increased losartan Cmax by 89%, and decreased estimated oral clearance by 51% in CYP2C91/1 subjects. [1]
- In the same cited review, E-3174 exposure decreased in parallel with the reduced metabolic conversion. [1]
Genotype-Dependent Risk
- The interaction magnitude differs by CYP2C9 genotype, with changes reported in CYP2C91/1 subjects and less effect reported in CYP2C91/3 carriers. [2]
Potential Clinical Consequences
- Reduced conversion of losartan to E-3174 can reduce antihypertensive effect attributable to the active metabolite. [3]
- Clinical decision support references note the potential for milk thistle to reduce losartan metabolism depending on CYP2C9 genotype. [3]
Management Considerations
- Medication review for CYP2C9-dependent therapy is recommended when milk thistle is used concurrently. [3]
- Clinical monitoring for blood pressure control changes is appropriate when milk thistle is initiated, continued, or discontinued during losartan therapy, given the documented pharmacokinetic changes. [1]
Common Pitfalls to Avoid
- Reliance on the absence of reported interaction with other CYP pathways is inappropriate when CYP2C9-mediated interaction with losartan has been demonstrated. [3]