Lack of P-glycoprotein induction by rifampicin and phenobarbital in human lymphocytes.
The efficacy of drugs acting within lymphocytes depends on their intracellular concentrations, which could be modulated by membrane efflux transporters including P-glycoprotein (P-gp), encoded by the MDR1 gene. In particular, P-gp induction may compromise the efficacy of its substrates. Rifampicin and phenobarbital have been shown to induce P-gp in hepatic and intestinal cells through the activation of the nuclear receptors PXR and CAR. However, controversial data exist in human lymphocytes. We investigated the effect of these drugs on P-gp activity and expression in lymphocytes in vitro and ex vivo. CCRF-CEM cells and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were incubated in the presence of rifampicin, phenobarbital, or without any drug. P-gp activity was measured by flow cytometry using DiOC(6) efflux. MDR1, PXR and CAR mRNA expression were measured by quantitative RT-PCR. Neither P-gp activity nor MDR1 mRNA expression were modified by rifampicin or phenobarbital both in CCRF-CEM cells and PBMCs. Moreover, P-gp protein expression at the membrane was neither detectable nor induced. The very weak PXR and CAR mRNA expression levels in these cells could partly explain these results. Therefore, P-gp induction by rifampicin and phenobarbital may play a negligible role in drug interactions occurring within lymphocytes.
Manceau
S
S
EA3620, Université Paris Descartes, Paris, France.
Giraud
C
C
Declèves
X
X
Batteux
F
F
Chouzenoux
S
S
Tang
R
R
Dauchy
S
S
Scherrmann
J M
JM
Weill
B
B
Morini
J P
JP
Perrot
J Y
JY
Tréluyer
J M
JM
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D004347:Drug Interactions; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D010634:Phenobarbital / Q000378:metabolism / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D012293:Rifampin / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D012293:Rifampin; D010634:Phenobarbital