Liquorice reduced cyclosporine bioavailability by activating P-glycoprotein and CYP 3A

► Liquorice activated P-gp and CYP3A4. ► Liquorice significantly decreased the oral bioavailability of cyclosporine. ► Liquorice is contraindicated for patients treated with cyclosporine. ► Concurrent use of liquorice with substrates of P-gp and CYP3A4 should be exercised with caution. Liquorice (root of Glycyrrhiza uralensis FISCH) is an ingredient of candies and used as a popular medicine in Europe and oriental countries. Cyclosporine (CsA), an immunosuppressant with narrow therapeutic window, is widely used in transplant patients. The absorption and disposition of CsA were associated with P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effects of liquorice extract (LE) and its major ingredient, glycyrrhizin (GZ), on CsA pharmacokinetics in rats. The results indicated that LE and GZ significantly decreased the peak blood concentration and the areas under the curves of CsA in rats. Mechanism studies revealed that glycyrrhetic acid (GA), the major metabolite of GZ, significantly activated the functions of P-gp and CYP3A4. In conclusion, liquorice significantly reduced the oral bioavailability of CsA through activating P-gp and CYP3A4.