Is quinine an inhibitor of P-glycoprotein and/or CYP3A4? Is there an interaction between tacrolimus

Fråga: Is quinine an inhibitor of P-glycoprotein and/or CYP3A4? Is there an interaction between tacrolimus and quinine?

A lung transplanted woman is treated with tacrolimus (Prograf) and has had stable concentrations of tacrolimus. Ten hours after one tablet 100 mg of quinine, for leg cramps, her concentration of tacrolimus increased about 2.5-fold.

Sammanfattning: Quinine is an inhibitor of P-glycoprotein and might interact with the P-glycoprotein substrate tacrolimus, leading to increased tacrolimus concentrations.

Svar: P-glycoprotein is a transport protein located in intestines, liver, kidney, blood-brain barrier, testis, placenta and lungs. P-glycoprotein protects the body from xenobiotics by efflux. For example P-glycoprotein inhibits the uptake of xenobiotics in the intestines and transports xenobiotics from the CNS back to the circulation reducing the level of substance in the brain. Many of the substances that are P-glycoprotein substrates are metabolised by CYP3A4 (1,2).

Many drugs are transported by P-glycoprotein, e.g. cytostatics, erythromycin, cyclosporin, tacrolimus, morphine, verapamil, quinidine, odansetrone, dexamethasone, indinavir and terphenadine (1, 2).

Tacrolimus is an immunosuppressive agent with a narrow therapeutic index. Drug interactions resulting in decreased or increased levels of tacrolimus might lead to severe complications like acute rejection or toxicity. Tacrolimus is largely metabolised in the liver and the intestinal mucosa by the CYP3A4. Tacrolimus is transported by P-glycoprotein and inibitors of CYP3A4 or P-glycoprotein might increase the levels of tacrolimus, leading to toxic levels (3).

Quinine is mainly metabolised into 3-hydroxyquinine by CYP3A4 (4). There is no clear evidence that quinine inhibits CYP3A4 although an interaction between quinine and other CYP3A4 substrates can not be excluded (5).

Quinine is a known inhibitor of P-glycoprotein. Multidrug resistance, a problem in cancer therapy, is caused by an overexpression of the MDR1 gene, which encodes for P-glycoprotein, leading to efflux of cytostatics from the cell. Quinine has been used to block P-glycoprotein and increase the concentration of cytostatics in cancer cells (6,7). 1 Levy RH, Thummel KE, Trager WF, Hansten PD, Eichelbaum M. Metabolic drug interactions. Philadelphia: Williams & Wilkins; 2000 2 Berglund EG, Gil JP. P-glykoprotein - ett betydelsefullt försvarsprotein mot främmande substanser och ett viktigt mål för läkemedelsinteraktioner. Info från Läkemedelsverket 2002;I:11-6. 3 Gelder T van. Drug interactions with tacrolimus. Drug Saf 2002;25(10):707-12. 4 Mirghani RA. Quinine metabolism in man. Emphasis on the 3-hydroxylation as a biomarker reaction for the activity of CYP3A4. Dissertation Stockholm: Karolinska Institute (2002) 5 Personal communication Rajaa Mirghani, Department of Clinical Pharmacology, Huddinge University Hospital 6 Wattel E, Solary E, Hecquet B, Caillot D, Ifrah N, et al. Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study. Br J Haematol 1998;102:1015-24. 7 Solary E, Drenou B, Campos L, de Cremoux P, Mugneret F, et al. Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia. Blood 2003;102:1202-10.