An inflammatory reaction could be an important source of intraindividual variability in cyclosporine pharmacokinetics, possibly through an inhibition of cytochrome P4503A-dependent enzyme activities by endogenous interleukin-6. Blood AM1 accumulation might be explained by a secondary metabolic step that is highly sensitive to the inhibitory effect of interleukin-6.

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The characteristics of the beta-adrenoceptors (3H-dihydroalprenolol binding) and the beta-adrenergic responsiveness (cyclic AMP response to isoproterenol) were studied in circulating lymphocytes from healthy volunteers before (D 0), on the 22nd day of treatment (D 22) and on the fifth day (D 30) following discontinuation of pindolol 15 mg/day or propranolol 160 mg/day. During pindolol therapy (D 22) the beta-adrenoceptor-affinity towards dihydroalprenolol was unchanged and the beta-adrenoceptor density decreased by 50%, an effect which persisted after drug administration ceased (D 30). The receptor "down-regulation" was accompanied by a parallel decrease in the maximal lymphocyte response to isoproterenol on D 22 and 30, by a shift to the right of the concentration-response curves to isoproterenol on D 22 and 30. In contrast, no significant modification in beta-adrenoceptor density or in the maximal response to isoproterenol was observed during (D 22) or after discontinuation (D 30) or propranolol therapy; the beta-adrenoceptor affinity for dihydroalprenolol and the sensitivity of the lymphocyte response to isoproterenol were markedly reduced on D 22 but not on D 30. It is concluded that the lymphocyte beta-adrenoceptor "down regulation" and the parallel beta-adrenergic desensitization induced by chronic pindolol therapy are both due to the intrinsic sympathomimetic activity of this drug.

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