Plasma 4β-Hydroxycholesterol Measurement as a Potential Biomarker for CYP3A5 Activity in Informing Tacrolimus Dosing

T. Elnahhas,^1,2 E. de Jonge,⁴ T. Lee,² B. van Zelst,⁴ J. Popoola,³ R. Ramkhelawon,³ R. van Schaik,⁴ A. Johnston,^1,2 I. MacPhee.³

¹Clinical Pharmacology, Queen Mary University of London, London, United Kingdom
²Analytical Services International, St.George's University of London, London, United Kingdom
³Institute of Medical and Biomedical Education-Renal Medicine, St.George's University of London, London, United Kingdom
⁴Clinical Chemistry, Erasmus MC Rotterdam, Rotterdam, Netherlands.

Meeting: 2015 American Transplant Congress

Abstract number: D113

Keywords: FK506, Gene polymorphism, Genomic markers, Kidney transplantation

Session Information

Session Name: Poster Session D: Kidney Immunosuppression: Drug Minimization

Session Type: Poster Session

Date: Tuesday, May 5, 2015

Session Time: 5:30pm-6:30pm

Presentation Time: 5:30pm-6:30pm

Location: Exhibit Hall E

Background—Recently, 4β-hydroxycholesterol (4β-OHC) has been shown to be an endogenous marker of P450 3A activity in clinical practice (Diczfalusy et al, 2011). 4β-OHC concentration increases with the number of active CYP3A5*1 alleles.

Objectives— The aim of this study was to investigate the relationship between genetically determined variation in CYP3A expression in comparison to the phenotypic marker 4β-OHC and tacrolimus pharmacokinetics in adult renal transplantation recipients.

Methods—Fifty nine patients aged between 21 to 76 years were included in this study. CYP3A5 genotype was determined using a Roche LightCycler®. Plasma 4β-OHC and tacrolimus blood concentrations were measured by liquid chromatography/tandem mass spectrometry. To correct 4β-hydroxycholesterol concentrations, total cholesterol was measured on Roche Modular P800 analyser. The data were analysed using analysis of variance (ANOVA). Correlation between variables was analysed by Pearson's product-moment correlation coefficient.

Results—The mean 4β-OHC/C for CYP3A5*1/*1(n=12), *1/*3 (n=16) and *3/*3 (n=31) genotypes were 7.64 ± 2.3, 7.09 ± 4.1 and 5.03 ± 2.0, respectively (P<0.01). Black subjects had significantly higher 4β-OHC concentrations in comparison to Whites (P=0.001) and Asian (P=0.011) and there was no significant difference between White and Asian subjects. The association with CYP3A5 genotype was preserved after exclusion of Black subjects. A significant correlation was observed between 4β-OHC/C and tacrolimus normalized Cmax (r = -0.29, p = 0.025), normalized AUC0-24 (r = -0.32, p = 0.014), normalized C0 (r = -0.29, p = 0.024) and normalized dose (r = 0.46, p > 0.001).

Conclusion—Plasma concentration of 4β-OHC was greater in CYP3A5 expressers. The 4β-OHC/C ratio was significantly correlated with tacrolimus exposure and dose requirement. We concluded that 4β-OHC/C ratio may be a useful biomarker for tacrolimus dosing in renal transplanted patients although it remains to be determined whether it would enhance predictions over CYP3A5 genotyping alone.

To cite this abstract in AMA style:

Elnahhas T, Jonge Ede, Lee T, Zelst Bvan, Popoola J, Ramkhelawon R, Schaik Rvan, Johnston A, MacPhee I. Plasma 4β-Hydroxycholesterol Measurement as a Potential Biomarker for CYP3A5 Activity in Informing Tacrolimus Dosing [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/plasma-4-hydroxycholesterol-measurement-as-a-potential-biomarker-for-cyp3a5-activity-in-informing-tacrolimus-dosing/. Accessed May 9, 2025.

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