Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites inseven kidney graft patients after the first dose of SDZ RAD

Aim The aim of the study was to investigate the pharmacokinetics and metabo lism of the new immunosuppressant SDZ RAD during concomitant therapy with c yclosporin in stable renal transplant patients. Furthermore, we studied the influence of SDZ RAD on the pharmacokinetics of cyclosporin at steady stat e levels. Methods SDZ RAD was administered orally in different doses (0.25-15 mg day( -1)) to seven patients, who were on standard cyclosporin-based immunosuppre ssion. The blood concentrations of both drugs including their main groups o f metabolites were measured simultaneously by LC/electrospray-mass spectrom etry. Results The mean area under the blood concentration-time curve to 12 h (AUC (0,12 h)) was 4244 +/- 1311 mug l(-1) h for cyclosporin before SDZ RAD trea tment and 4683 +/- 1174 mug l(-1) h (P = 0.106) on the day of SDZ RAD treat ment (95% CI for difference -126, 1003). On both study days C-max, and t(ma x) of cyclosporin were not significantly different. The metabolite pattern of cyclosporin did not change. The pharmacokinetic data of SDZ RAD dose-nor malized to 1 mg SDZ RAD were as follows: AUC(0,24 h): 35.4 +/- 13.1 mug l(- 1) h, C-max: 7.9 +/- 2.7 mug l(-1) and t(max): 1.5 +/- 0.9 h. The metabolit es of SDZ RAD found in blood were hydroxy-SDZ RAD, dihydroxy-SDZ RAD, demet hyl-SDZ RAD, and a ring-opened form of SDZ RAD. Conclusions A single dose of SDZ RAD did not influence significantly the ph armacokinetics of cyclosporin. The most important metabolite of SDZ RAD was the hydroxy-SDZ RAD, its AUC(0,24 h) being nearly half that of the parent compound SDZ RAD.