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08:38
Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
Published on: November 8, 2015
Genetic differences in Native Americans and tacrolimus dosing after kidney transplantation
H A Chakkera1, Y-H Chang, J K Bodner
1Division of Nephrology, Mayo Clinic, Phoenix, Arizona 85054, USA. chakkera.harini@mavo.edu
Transplantation Proceedings
|February 5, 2013
Summary
Native Americans require lower tacrolimus doses due to genetic variations affecting drug metabolism and excretion. These single nucleotide polymorphisms (SNPs) alter drug clearance, necessitating dose adjustments for optimal therapeutic levels in kidney transplant patients.
Area of Science:
- Pharmacogenomics
- Transplantation Medicine
- Drug Metabolism
Background:
- Tacrolimus pharmacokinetics are influenced by genetic variations in drug-metabolizing enzymes and transporters.
- Clinical observations indicate Native Americans require lower tacrolimus doses than Caucasians to achieve similar therapeutic trough levels.
- Previous studies showed Native Americans have decreased oral tacrolimus clearance, suggesting a higher prevalence of genetic variants.
Purpose of the Study:
- To investigate the pharmacokinetic differences of tacrolimus between Native American and Caucasian kidney transplant recipients.
- To identify specific single nucleotide polymorphisms (SNPs) in key genes (CYP3A4, CYP3A5, ABCB1, BCRP, MRP1) associated with altered tacrolimus metabolism and transport.
- To correlate genetic findings with observed differences in tacrolimus dosing requirements.
Main Methods:
- Conducted 12-hour pharmacokinetic studies in 24 Native American and 24 Caucasian kidney transplant recipients on stable tacrolimus therapy.
- Genotyped SNPs in genes encoding CYP3A4, CYP3A5, ABCB1, BCRP, and MRP1 using TaqMan assays.
- Compared daily tacrolimus doses (mg/kg/d) and trough levels (ng/dL) between the two ethnic groups.
Main Results:
- Native Americans required significantly lower mean daily tacrolimus doses (0.03 ± 0.02 mg/kg/d) compared to Caucasians (0.5 ± 0.3 mg/kg/d; P = .002).
- No significant differences in tacrolimus trough levels were observed between groups (6.7 ± 3.1 vs 7.4 ± 2.1 ng/dL; P = .4).
- A higher prevalence of specific genotype combinations (e.g., 3/*3 - C3435T CC and *3/*3 -G2677T GG) associated with low tacrolimus dosing was found in Native Americans.
Conclusions:
- Native Americans require significantly lower tacrolimus doses than Caucasians to achieve comparable therapeutic trough levels.
- Decreased tacrolimus clearance in Native Americans is partly attributed to reduced drug metabolism and excretion, driven by specific genetic polymorphisms.
- These findings highlight the importance of pharmacogenomic profiling for personalized tacrolimus dosing in kidney transplant recipients.
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