Induction of P‐glycoprotein in lymphocytes by carbamazepine and rifampicin: the role of nuclear hormone response elements

AIMS: Carbamazepine (CBZ) is an inducer of cytochrome P450 enzymes, which have been implicated in many drug interactions. However, for immunosuppressant and anti-HIV drugs, whose main site of action is the lymphocyte, induction of P-glycoprotein (Pgp) may also be important. In this study, we have investigated whether CBZ acts as an inducer of Pgp in lymphocytes. METHODS: Pgp expression was assessed by flow cytometry and real-time reverse transcriptase-polymerase chain reaction using lymphocytes from four healthy subjects after incubation with therapeutic concentrations of CBZ, using rifampicin as a positive control. Binding to DR-4 elements in the MDR1 promoter was assessed by electrophoretic mobility shift assay (EMSA) and a luciferase-reporter construct. RESULTS: CBZ increased MDR1 mRNA expression at 6 h by 3.7-fold [95% confidence interval (CI) 0, 7.6) when compared with controls. CBZ increased lymphocyte Pgp expression at 72 h by 7.6-fold (95% CI 2.1, 13.2) over control values. EMSA revealed a 2.1-fold (95% CI 1.5, 2.7) increased binding to the DR-4 element of CBZ when compared with control values. Activation of the DR-4 element was confirmed using reporter constructs. Rifampicin also had similar effects in all experiments. CONCLUSIONS: Carbamazepine induces Pgp in a manner comparable to rifampicin, by increasing binding to the DR4 element. This has implications for interactions involving drugs whose site of action is the lymphocyte.