Effect of active infection on cytochrome P450-mediated metabolism of cyclosporine in renal transplant patients

Background: Infections downregulate cytochrome-P activities and thus may alter drug disposition, especially for drugs with a narrow therapeutic index. Cyclosporine (CyA), still used for the prevention of allograft rejection in renal transplant recipients in Egypt, seems to be affected by these infectious changes, based on random clinical observations. In the present study, the effects of bacterial and fungal infection on CyA metabolism were studied in renal transplant patients and subsequent nephrotoxicity was monitored.

Methods: Twenty renal transplant patients, diagnosed with fungal or bacterial infection, were recruited from the renal transplantation outpatient clinic in Alexandria University Hospitals. No dose adjustment in CyA was performed at least 1 week before the onset of infection. Exclusion criteria were patients with acute or chronic unstable liver disease, elderly patients, and patients on concomitant drugs affecting CyA metabolism. CyA trough levels and serum creatinine (SCR) concentrations were measured by fluorescence polarization immunoassay and enzymatic assay, respectively, pre-infection, during infection and in many cases, post infection.

Results: CyA trough levels and SCR concentrations increased significantly during the infection (P < 0.001, P = 0.002) respectively. Of the patients, 87% experienced a concomitant rise in CyA trough level and SCR concentrations. No significant difference between pre-infection and post-infection levels of CyA trough and SCR was found.

Conclusions: CyA trough and SCR levels increased during bacterial and fungal infections and returned to pre-infection levels once the infection was resolved. The data generated stress the importance of monitoring CyA levels during episodes of infection. Our recommendations concerning CyA dose adjustment differ according to severity and duration of infection.