Immunosuppressive Interactions among Calcium Channel Antagonists and Selected Corticosteroids and Macrolides Using Human whole Blood Lymphocytes

Abstract

The immunosuppressive interactions of calcium channel antagonists [diltiazem (Dil), verapamil (Ver) and nifedipine (Nif)], with corticosteroids [methylprednisolone (Mpl), prednisolone (Prd)], and macrolides [tacrolimus (Tac) and sirolimus (Sir)] were examined in human whole blood lymphocyte cultures. Gender-related differences in responses in the interactions between these drug classes were studied using blood from 6 males and 6 females. The nature and intensity of interactions were determined using an extended Loewe additivity model. All immunosuppressants exhibited higher potency than the calcium channel antagonists with mean IC50 values of: Dil Ver Nif Mpl Prd Tac Sir (mM) (mM) (mM) (nM) (nM) (nM) (nM) Male 135 41.9 213 12.1 18.6 150 327 Female 114 31.8 47.4 4.6 8.8 111 106 Gender-related differences in responses to Mpl and Prd were observed while the others were not significant. Additive interactions were found among calcium channel antagonists and corticosteroids. Significant synergistic interactions were observed between calcium channel antagonists and tacrolimus and sirolimus, although these are unlikely to be of clinical importance. These studies demonstrate diverse drug interactions in the examination of an important array of immunosuppressant drug combinations.