CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients.
It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 -24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67+/-0.3 and 1.36+/-0.73 x 10(3) l (P<0.00001) for tacrolimus and 0.42+/-0.17 and 0.84+/-0.46 x 10(3) l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)(0-12) was 106.8+/-17.5 ng/ml x h compared with 133.3+/-42.2 ng/ml x h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC(0-24) of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles.
Renders
L
L
Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Frisman
M
M
Ufer
M
M
Mosyagin
I
I
Haenisch
S
S
Ott
U
U
Caliebe
A
A
Dechant
M
M
Braun
F
F
Kunzendorf
U
U
Cascorbi
I
I
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D011239:Prednisolone / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D020123:Sirolimus / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016559:Tacrolimus / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use
C000715087:ABCC2 protein, human; D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D003577:Cytochrome P-450 Enzyme System; D011239:Prednisolone; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus