Impact of CYP3A5 and MDR1(ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients.

Abstract

OBJECTIVE:

The objective of this study was to assess the influence of CYP3A5 and MDR1 genetic polymorphisms on tacrolimus pharmacokinetics in Japanese renal transplant recipients.

METHOD:

The pharmacokinetic parameters of tacrolimus were calculated in steady-state on day 28 after transplantation. Polymerase chain reaction-restriction fragment length polymorphism and direct sequence methods were used for CYP3A5 and MDR1 polymorphisms, respectively.

RESULTS:

The dose-adjusted area under the concentration-time curve (AUC0-12) was significantly lower among CYP3A5*1 carriers than those bearing CYP3A5*3/*3. (0.570 +/- 0.105 vs 0.865 +/- 0.343 ng.h/mL per mg/kg, P = .00322). The daily tacrolimus dose per body weight was significantly higher in CYP3A5*1 carriers than those of CYP3A5*3/*3 carriers (0.271 +/- 0.110 vs 0.150 +/- 0.056 mg/kg, P = .00016). In this study, a distinction was made between carriers of CYP3A5*1/*1+*1/*3 and CYP3A5*3/*3 to investigate the influence of the MDR1 C3435T mutation on tacrolimus pharmacokinetics. The MDR1 C3435T polymorphisms did not affect any tacrolimus pharmacokinetic parameter in either group.

CONCLUSIONS:

Renal transplant recipients who were CYP3A5*1 carriers required a higher dose of tacrolimus than CYP3A5*3/*3, indicating a significantly lower dose-adjusted AUC0-12 of tacrolimus. In contrast, MDR1 C3435T polymorphism was not an important factor in tacrolimus pharmacokinetics.

• Authors: H Tada, N Tsuchiya, S Satoh, H Kagaya, Z Li, K Sato, M Miura, T Suzuki, T Kato, T Habuchi
• Journal: Transplantation proceedings (Transplant Proc) Vol. 37 Issue 4 Pg. 1730-2 (May 2005) ISSN: 0041-1345 [Print] United States
• PMID: 15919447 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Immunosuppressive Agents
• Cytochrome P-450 Enzyme System
• CYP3A protein, human
• CYP3A5 protein, human
• Cytochrome P-450 CYP3A
• Tacrolimus

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• Area Under Curve
• Cytochrome P-450 CYP3A
• Cytochrome P-450 Enzyme System (genetics)
• Genetic Carrier Screening
• Genotype
• Humans
• Immunosuppressive Agents (pharmacokinetics, therapeutic use)
• Kidney Transplantation (physiology)
• Polymerase Chain Reaction
• Polymorphism, Restriction Fragment Length
• Polymorphism, Single Nucleotide
• Tacrolimus (pharmacokinetics, therapeutic use)