[Interaction between sildenafil and calcineurin inhibitors in renal transplant recipients with erectile dysfunction].
OBJECTIVE
Hepatic metabolism of sildenafil uses the same metabolic pathway as the calcineurin inhibitors (cyclosporine/tacrolimus), through the CYP3A4 isoenzyme. The aim of this pilot study was to evaluate the potential interaction between sildenafil therapy and circulating levels of cyclosporine and tacrolimus in a group of steady-state renal transplant recipients with erectile dysfunction.


METHODS
A prospective pilot study of sildenafil interactions was carried out in 9 stable male renal transplant recipients with severe erectile dysfunction (mean age 50 +/- 8 years, range 38-64). All patients were receiving therapy with calcineurin inhibitors (5 with cyclosporine and 4 with tacrolimus). Erectile dysfunction was evaluated by clinical history, physical examination, International Index of Erectile Function (IIEF) questionnaire and the nocturnal penile tumescence test (RigiScan). Each patient received a first dose of 50 mg of sildenafil, one hour before sexual activity and a second dose at 72 hours of 50 or 100 mg according to the clinical response to the first dose. We evaluated the efficacy and safety of sildenafil and the evolution of cyclosporine-tacrolimus levels. Cyclosporine and tacrolimus trough whole blood concentrations were determined in basal conditions (before starting sildenafil) and on days 1, 4 and 7 after sildenafil therapy.


RESULTS
Eighty-nine percent of patients (n = 8) required a complete 100 mg dose of sildenafil. There was a positive clinical response in two-thirds of cases (6 patients). In 5 patients (55%) sildenafil administration produced a complete response, in one patient the response was incomplete, and in the remaining 3 cases (33%) no clinical response was observed. Associated side effects included self-limited tachycardia in one patient and mild visual disturbances in another. Cyclosporine and tacrolimus levels remained stable in all patients. There were no significant differences in circulating levels of cyclosporine (basal 120 +/- 47; day 1: 116 +/- 55; day 4: 123 +/- 56 and day 7: 121 +/- 56 ng/ml p = NS) or tacrolimus (basal 11.6 +/- 1.3; day 1: 11.9 +/- 1.3; day 4: 11.1 +/- 1.0 and day 7: 11.8 +/- 0.9 ng/ml p = NS) over the study period.


CONCLUSIONS
Sildenafil therapy is safe and effective for the treatment of erectile dysfunction in renal transplant recipients. Recommended therapeutic doses of sildenafil did not modify cyclosporine and tacrolimus trough blood levels.
Cofán
F
F
Unidad de Trasplante Renal, Universidad de Barcelona, Barcelona. fcofan@medicina.ub.es
Gutiérrez
R
R
Beardo
P
P
Campistol
J M
JM
Oppenheimer
F
F
Alcover
J
J
D000328:Adult; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008658:Inactivation, Metabolic; D016030:Kidney Transplantation; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008875:Middle Aged; D010865:Pilot Projects; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011687:Purines; D012449:Safety; D000068677:Sildenafil Citrate; D013450:Sulfones; D013610:Tachycardia / Q000139:chemically induced; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D000068677:Sildenafil Citrate; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus