Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites in seven kidney graft patients after the first dose of SDZ RAD.
OBJECTIVE
The aim of the study was to investigate the pharmacokinetics and metabolism of the new immunosuppressant SDZ RAD during concomitant therapy with cyclosporin in stable renal transplant patients. Furthermore, we studied the influence of SDZ RAD on the pharmacokinetics of cyclosporin at steady state 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 immunosuppression. The blood concentrations of both drugs including their main groups of metabolites were measured simultaneously by LC/electrospray-mass spectrometry.


RESULTS
The mean area under the blood concentration-time curve to 12 h (AUC(0,12 h)) was 4244 +/- 1311 microg l-1 h for cyclosporin before SDZ RAD treatment and 4683 +/- 1174 microg l-1 h (P = 0.106) on the day of SDZ RAD treatment (95% CI for difference -126, 1003). On both study days Cmax, and tmax of cyclosporin were not significantly different. The metabolite pattern of cyclosporin did not change. The pharmacokinetic data of SDZ RAD dose-normalized to 1 mg SDZ RAD were as follows: AUC(0,24 h): 35.4 +/- 13.1 microg l-1 h, Cmax: 7.9 +/- 2.7 microg l-1 and tmax: 1.5 +/- 0.9 h. The metabolites of SDZ RAD found in blood were hydroxy-SDZ RAD, dihydroxy-SDZ RAD, demethyl-SDZ RAD, and a ring-opened form of SDZ RAD.


CONCLUSIONS
A single dose of SDZ RAD did not influence significantly the pharmacokinetics 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.
Kirchner
G I
GI
Institute for General Pharmacology, Medical School of Hannover, Germany. Kirchner.Gabriele@MH-Hannover.DE
Winkler
M
M
Mueller
L
L
Vidal
C
C
Jacobsen
W
W
Franzke
A
A
Wagner
S
S
Blick
S
S
Manns
M P
MP
Sewing
K F
KF
D000284:Administration, Oral; D000328:Adult; D002853:Chromatography, Liquid; D017321:Clinical Trials, Phase I as Topic; D016572:Cyclosporine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D003524:Cyclosporins / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007166:Immunosuppressive Agents / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D021241:Spectrometry, Mass, Electrospray Ionization
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C051527:cyclosporine metabolite M17; D000068338:Everolimus; D020123:Sirolimus