Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate-binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms.
Tacrolimus, an immunosuppressant used after organ transplantation, has a narrow therapeutic range and its pharmacokinetic variability complicates its daily dose assessment. P-glycoprotein (P-gp), encoded by the adenosine triphosphate-binding cassette B1 (ABCB1) and the cytochrome (CYP) 3A4 and 3A5 enzymes appears to play a role in the tacrolimus metabolism. In the present study, two different renal transplant recipient groups were used to examine the influence of ABCB1 and CYP3A polymorphisms on the daily tacrolimus dose and several pharmacokinetic parameters. In total 63 Caucasian renal transplant recipients divided into 26 early [median (range) of the days since transplantation - 16 (3-74)] and 37 late [median (range) of the days since transplantation - 1465 (453-4128)] post-transplant recipients were genotyped for ABCB1 and CYP3A polymorphisms. The pharmacokinetic parameters of tacrolimus were determined for all renal transplant recipients and correlated with their corresponding genotypes. A significant difference in allele frequencies of the CYP3A4*1B (P = 0.028) and CYP3A5*1 (P = 0.022) alleles was observed between the early and late post-transplant recipient groups. Significantly higher dose-normalized trough levels (dnC(0)), dose-normalized area under the curve (dnAUC(0-12)), and dose-normalized maximum concentration (dnC(max)) were observed for carriers of the CYP3A5*3 variant allele in both renal transplant patient groups. Except for the daily tacrolimus dose (P = 0.025) no significant differences were observed for carriers of the CYP3A4*1B variant allele. Neither the individual ABCB1 polymorphisms nor the ABCB1 haplotypes were associated with any pharmacokinetic parameter. We noticed that patients carrying a CYP3A5*1 allele require a twofold higher tacrolimus dose compared with homozygous carriers of the CYP3A5*3 variant allele to maintain the target dnAUC(0-12). Therefore, genotyping for the CYP3A5*3 variant allele can contribute to a better and more individualized immunosuppressive therapy in transplant patients.
Op den Buijsch
Robert A M
RA
Department of Clinical Chemistry, University Hospital Maastricht, Maastricht, The Netherlands.
Christiaans
Maarten H L
MH
Stolk
Leo M L
LM
de Vries
Johan E
JE
Cheung
Chi Yuen
CY
Undre
Nas A
NA
van Hooff
Johannes P
JP
van Dieijen-Visser
Marja P
MP
Bekers
Otto
O
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044465:White People
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus