The effects of P-gp and CYP450 modulated by rifampicin on the steroid-induced osteonecrosis of the femoral head.

Abstract

This study investigated the effects of rifampicin-modulated P-glycoprotein (P-gp) and cytochrome P450 (CYP450) activity on the development of steroid-induced osteonecrosis of the femoral head. Thirty-two rabbits were equally divided into four groups: control group, oral administration group, intramuscular injection group, and local release group, in which rifampicin-loaded artificial bone graft was implanted in the left femur cavity and blank bone graft was implanted in the right femur cavity. Dexamethasone was given 1week after rifampicin administration. Peripheral P-gp activity and hepatic CYP450 content were investigated 4weeks later. Hematoxylin and eosin, Massson, and tetracycline-fluorescence staining of the femoral head were compared. In vitro, the effects of intracellular dexamethasone concentration modulated by P-gp on osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL) expression and differentiation of mesenchymal stem cells were further investigated. Peripheral P-gp activity and hepatic CYP450 content in the oral administration group and the intramuscular injection group were significantly higher than those in the local release group. P-gp activity of mesenchymal stem cells in rifampicin-implanted femoral head was significantly higher than that in the blank control. Histological study showed that rifampicin could prevent steroid-induced bone loss and lipid formation, and promote new bone formation and maturation. In vitro study confirmed that intracellular dexamethasone concentration modulated by P-gp could influence the OPG/RANKL ratio and the differentiation of mesenchymal stem cells. Enhanced levels of peripheral P-gp and hepatic CYP450 can reduce the incidence of steroid-induced osteonecrosis of the femoral head. P-gp activity locally enhanced by rifampicin decreases the intracellular steroid concentration, but rifampicin does not have significant effects on peripheral P-gp and hepatic CYP450.