Relationship between In Vivo CYP3A4 Activity, CYP3A5 Genotype, and Systemic Tacrolimus Metabolite/Parent Drug Ratio in Renal Transplant Recipients and Healthy Volunteers

Abstract

CYP3A5 genotype is a major determinant of tacrolimus clearance, and has been shown to affect systemic tacrolimus metabolite/parent ratios in healthy volunteers, which may have implications for efficacy and toxicity. In a cohort of 50 renal transplant recipients who underwent quantification of CYP3A4 activity using the oral midazolam drug probe, we confirmed that CYP3A5 genotype is the single most important determinant of tacrolimus metabolite/parent ratio [CYP3A5 expressors displayed 2.7- and 2-fold higher relative exposure to 13-desmethyltacrolimus (DMT) and 31-DMT, respectively; < 0.001]. There was, however, no relationship between CYP3A4 activity and tacrolimus metabolite/parent ratios. Additional analyses in 16 healthy volunteers showed that dual pharmacological inhibition of CYP3A4 and P-glycoprotein using itraconazole resulted in increased tacrolimus metabolite/parent ratios (+65%, +112%, and 25% for 13-, 15-, and 31-DMT, respectively; < 0.01). This finding was confirmed in a cohort of nine renal transplant recipients who underwent tacrolimus pharmacokinetic assessments before and during CYP3A4 inhibition (58% increase in overall metabolite/tacrolimus ratio; = 0.017).

Tacrolimus induces a pro-fibrotic response in donor-derived human proximal tubule cells dependent on common variants of theCYP3A5andABCB1genes

“…Our previous data on the metabolism of tacrolimus in ciPTC confirmed a substantially higher rate of tacrolimus metabolism in *1 allele carriers, in line with findings in human liver microsome [40] and clinical data [19,37,41]. In this study, ciPTC with this genetic background also demonstrated a higher absolute and relative propensity for the formation of the M1 metabolite, which was most pronounced in cells with the additional TT genotype.…”

Conversion from Standard-Release Tacrolimus to MeltDose® Tacrolimus (LCPT) Improves Renal Function after Liver Transplantation

“…Therefore, we can only hypothesize that, after conversion to LCPT, lower C 2 was a more relevant factor to the improvement of renal function than trough level reduction. Further investigations should also include data on the concentrations of different Tac metabolites, which could be responsible for adverse effects, such as CNIT, infections and myelotoxicity [38,39]. Furthermore, given the retrospective design of this study, the study beginning in the control group had a wide range from March 2017 until August 2018 and the time period from LTx to the beginning of the study was significantly increased compared with that in the intervention group.…”

Prolonged‐Release Tacrolimus Is Less Susceptible to Interaction With the Strong CYP3A Inhibitor Voriconazole in Healthy Volunteers

“…Tacrolimus is metabolized by CYP3A4 and CYP3A5 and is a substrate of the drug transporter P‐glycoprotein . Patients carrying at least one functional CYP3A5 allele (CYP3A5*1) require approximately twofold higher oral tacrolimus doses than patients homozygous for CYP3A5*3 and appear to be less susceptible to drug–drug interactions with azole antimycotics, which may be explained by stronger inhibition of CYP3A4 than CYP3A5 by azoles . High expression of intestinal ABCB1 messengerRNA (mRNA) (which is translated into P‐glycoprotein) was related to higher dose requirements, but several common ABCB1 polymorphisms were not related to tacrolimus pharmacokinetics, suggesting that P‐glycoprotein is of lesser importance in oral tacrolimus pharmacokinetics.…”