23, 40, 42, 50, 51 These genotypes are also associated with delays in achieving therapeutic concentrations. 14, 48, 49 Therefore, the dose requirements for CYP3A5*1/*1 or *1/*3 carriers are ~1.5–1.7-fold higher than CYP3A5*3/*3 carriers. 45, 46, 47 The presence of the CYP3A5*3 allele is associated with lower oral tacrolimus clearance (Cl/F), whereas the CYP3A5*1 allele is associated with high Cl/F ( CYP3A5*1/*1 individuals ~1 l h −1 kg −1 CYP3A5*1/*3 ~0.8 l h −1 kg −1 vs CYP3A5*3/*3 ~0.5 l h −1 kg −1). 23, 30, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44ĬYP3A5*3 is an intronic variant that generates a cryptic splice site resulting in a nonfunctional enzyme. 32, 33 Genetic variants associated with CYP3A5, CYP3A4, P450 (cytochrome) oxidoreductase (POR) and P-glycoprotein have been studied for their influence on tacrolimus clearance, although only CYP3A5 variants have demonstrated major clinical relevance. 31 Tacrolimus is also a substrate of P-glycoprotein that is an efflux transporter expressed on enterocytes. 14, 30 CYP3A5 is a more efficient catalyst of tacrolimus metabolism as compared with CYP3A4. Tacrolimus is metabolized by hepatic and intestinal CYP3A4 and CYP3A5 enzymes. 24, 25, 26, 27, 28, 29 However, not all AAs will require a higher dose and these individuals may have nonfunctional genetic variants that lead to reduced metabolic capacity similar to Caucasians. 19, 20, 21, 22, 23 To achieve target tacrolimus trough concentrations some AAs require ~1.5 to 2 times higher doses than Caucasians. 17, 18 There is a significant difference in tacrolimus pharmacokinetics by race where AAs have 20–50% lower bioavailability, higher clearance and lower blood concentrations as compared with Caucasians. 14, 15, 16 This necessitates therapeutic drug monitoring to avoid subtherapeutic and supratherapeutic concentrations that place the recipient at risk of rejection and toxicity, respectively. Tacrolimus has a narrow therapeutic index 9, 10, 11, 12, 13 with wide interindividual variability in pharmacokinetics resulting in unpredictable blood concentrations. 3, 4, 5, 6 There are several reasons cited for poor outcomes including greater variation in human leukocyte antigen, immunological differences, higher medical nonadherence, socioeconomic barriers and pharmacokinetic differences of the immunosuppressive agents including tacrolimus. 1, 2 Long-term graft survival rates are lower and all-cause mortality rates are higher in AAs than in Caucasians or Asians. African Americans (AAs) represent ∼34% of the candidates in the kidney transplant waiting list. Kidney transplantation is a common and effective treatment for end-stage renal disease.
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