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Induction of P‐glycoprotein in lymphocytes by carbamazepine and rifampicin: the role of nuclear hormone response elements
Author(s) -
Owen Andrew,
Goldring Chris,
Morgan Paul,
Park B. Kevin,
Pirmohamed Munir
Publication year - 2006
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2006.02587.x
Subject(s) - carbamazepine , pharmacology , inducer , rifampicin , chemistry , microbiology and biotechnology , lymphocyte , p glycoprotein , enzyme inducer , flow cytometry , biology , enzyme , biochemistry , immunology , antibiotics , neuroscience , multiple drug resistance , epilepsy , gene
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.