AUTHOR=Brazeau Daniel A. , Attwood Kristopher , Meaney Calvin J. , Wilding Gregory E. , Consiglio Joseph D. , Chang Shirley S. , Gundroo Aijaz , Venuto Rocco C. , Cooper Louise , Tornatore Kathleen M. 

TITLE=Beyond Single Nucleotide Polymorphisms: CYP3A5∗3∗6∗7 Composite and ABCB1 Haplotype Associations to Tacrolimus Pharmacokinetics in Black and White Renal Transplant Recipients

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.00889

DOI=10.3389/fgene.2020.00889

ISSN=1664-8021

ABSTRACT=<p>Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A5 (CYP3A5) isoenzymes and membrane transport by P-glycoprotein. Interpatient pharmacokinetic variability has been associated with genotypic variants for both <italic>CYP3A5</italic> or <italic>ABCB1</italic>. Tacrolimus pharmacokinetics was investigated in 65 stable Black and Caucasian post-renal transplant patients by assessing the effects of multiple alleles in both <italic>CYP3A5</italic> and <italic>ABCB1.</italic> A metabolic composite based upon the <italic>CYP3A5</italic> polymorphisms: <italic><sup>∗</sup>3</italic>(rs776746), <italic><sup>∗</sup>6</italic>(10264272), <italic>and <sup>∗</sup>7(41303343</italic>), each independently responsible for loss of protein expression was used to classify patients as extensive, intermediate and poor metabolizers. In addition, the role of <italic>ABCB1</italic> on tacrolimus pharmacokinetics was assessed using haplotype analysis encompassing the single nucleotide polymorphisms: <italic>1236C</italic> &gt; <italic>T (rs1128503), 2677G</italic> &gt; <italic>T/A(rs2032582), and 3435C</italic> &gt; <italic>T(rs1045642)</italic>. Finally, a combined analysis using both <italic>CYP3A5</italic> and <italic>ABCB1</italic> polymorphisms was developed to assess their inter-related influence on tacrolimus pharmacokinetics. Extensive metabolizers identified as homozygous wild type at all three <italic>CYP3A5</italic> loci were found in 7 Blacks and required twice the tacrolimus dose (5.6 ± 1.6 mg) compared to Poor metabolizers [2.5 ± 1.1 mg (P &lt; 0.001)]; who were primarily Whites. These extensive metabolizers had 2-fold faster clearance (<italic>P</italic> &lt; 0.001) with 50% lower AUC<sup>∗</sup> (<italic>P</italic> &lt; 0.001) than Poor metabolizers. No differences in C<sub>12 <italic>h</italic></sub> were found due to therapeutic drug monitoring. The majority of blacks (81%) were classified as either Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. Blacks who were homozygous for one or more loss of function SNPS were associated with lower tacrolimus doses and slower clearance. These values are comparable to Whites, 82% of who were in the Poor metabolic composite group. The <italic>ABCB1</italic> haplotype analysis detected significant associations of the wildtype <italic>1236T-2677T-3435T</italic> haplotype to tacrolimus dose (<italic>P</italic> = 0.03), CL (<italic>P</italic> = 0.023), CL/LBW (<italic>P</italic> = 0.022), and AUC<sup>∗</sup> (<italic>P</italic> = 0.078). Finally, analysis combining <italic>CYP3A5</italic> and <italic>ABCB1</italic> genotypes indicated that the presence of the <italic>ABCB1</italic> 3435 T allele significantly reduced tacrolimus clearance for all three CPY3A5 metabolic composite groups. Genotypic associations of tacrolimus pharmacokinetics can be improved by using the novel composite <italic>CYP3A5<sup>∗</sup>3<sup>∗</sup>4<sup>∗</sup>5 and ABCB1</italic> haplotypes. Consideration of multiple alleles using <italic>CYP3A5</italic> metabolic composites and drug transporter ABCB1 haplotypes provides a more comprehensive appraisal of genetic factors contributing to interpatient variability in tacrolimus pharmacokinetics among Whites and Blacks.</p>