Clinical association among tacrolimus dose requirement, CYP3A genotypes, and the concentrations of urinary endogenous CYP3A biomarkers in lung transplant recipients: A cross-sectional study

Background: Tacrolimus (TAC), an immunosuppressive drug used to prevent graft rejection in patients undergoing organ transplantation, is primarily metabolized by cytochrome P450 3A (CYP3A). Therapeutic drug monitoring (TDM) in patients receiving TAC is routinely performed in clinical practice to help maintain the TAC dose; however, determination of the initial TAC dose is primarily based on body weight. This study evaluated the relationship among TAC dose requirements, CYP3A genotypes, and urinary endogenous CYP3A biomarker concentrations in patients who underwent lung transplantation. Methods: In this cross-sectional study, the concentrations of blood TAC and urinary CYP3A biomarkers (1β-hydroxydeoxycholic acid, 6β-hydroxycortisol, deoxycholic acid, and cortisol) from 57 patients who were administered TAC continuously and had stably managed blood TAC concentrations were quantified via immunoassays and liquid chromatography–tandem mass spectrometry, respectively. Genotyping was performed using polymerase chain reaction–based Sanger sequencing. Additionally, stepwise regression analysis was conducted to evaluate the best parameters for predicting the TAC dose. Results: TAC dose was significantly associated with CYP3A genotypes, whereas there was no correlation between TAC dose and endogenous urinary CYP3A biomarkers. Overall, two variant alleles, CYP3A4∗1G and CYP3A5∗3, were significantly associated with TAC dose. The CYP3A4∗1G and CYP3A5∗3 variants are known to affect enzyme activity, with CYP3A5∗3 leading to decreased expression of CYP3A5, which can alter TAC metabolism and thereby affect dosing requirements.Notably, the CYP3A5 genotype information parameter was built into the model using both Akaike's Information Criterion and Bayesian Information Criterion strategies. Conclusions: This study highlights the utility of CYP3A genotyping and endogenous urinary CYP3A biomarkers for predicting blood trough TAC concentrations. These findings provide valuable insights into enhanced TDM and contribute to the advancement of personalized medicine.