tacrolimus and cholest-5-ene-3-4-diol

CYP3A enzymes are involved in the metabolism of calcineurin inhibitor tacrolimus as well as vitamin D. In this review, we summarize the clinical aspects of CYP3A-mediated metabolism of tacrolimus and vitamin D with emphasis on the influence of single-nucleotide polymorphisms on tacrolimus disposition. We describe the utility of 4β hydroxycholesterol as a marker of CYP3A activity. Then, we discuss the possible interaction between calcineurin inhibitors and vitamin D in solid organ transplant recipients. Also, we review other mechanisms which may contribute to side effects of calcineurin inhibitors on bone. Lastly, suggestions for future research and clinical perspectives are discussed.

Topics: Animals; Biomarkers; Bone Density; Bone Diseases, Metabolic; Calcineurin Inhibitors; Cytochrome P-450 CYP3A; Humans; Hydroxycholesterols; Kidney Transplantation; Polymorphism, Single Nucleotide; Tacrolimus; Vitamin D

This study aimed to evaluate the relationships between concomitant biologic disease-modifying anti-rheumatic drugs (DMARDs) and prednisolone administration and blood tacrolimus exposure or serum CYP3A4/5-related markers in rheumatoid arthritis (RA) patients without severe disease activity.. Forty-six RA patients treated with oral tacrolimus once daily for maintenance of clinical remission to moderate disease activity were enrolled. The blood concentrations of tacrolimus and its major metabolite were determined at 12 h after the evening dosing. Blood samples for determination of serum markers including 4β-hydroxycholesterol (4β-OHC), 25-hydroxyvitamin D (25-OHD) and interleukin-6 (IL-6), and CYP3A5 genotype were collected.. Most enrolled patients had RA with clinical remission to mild disease activity. Concomitant tocilizumab or low-dose prednisolone administration did not alter the blood tacrolimus exposure. Serum 4β-OHC level was lower in tocilizumab co-treated patients than in the biologic DMARD non-treated patients. The blood tacrolimus concentration was inversely correlated with the serum level of 25-OHD, but not 4β-OHC and IL-6. The serum level of 4β-OHC was positively associated with that of 25-OHD. No correlations were observed between the serum levels of CYP3A4/5 activity markers and IL-6. The patients with the homozygous CYP3A5*3 had the higher blood tacrolimus concentration, while CYP3A5*3 allele was not associated with the serum levels of 4β-OHC and 25-OHD.. Concomitant use of tocilizumab or low-dose prednisolone had no effect on the pharmacokinetics of tacrolimus, while tocilizumab lowered serum 4β-OHC. Blood tacrolimus exposure was negatively associated with serum 25-OHD in RA patients with clinical remission to moderate disease activity.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Cytochrome P-450 CYP3A; Female; Humans; Hydroxycholesterols; Immunosuppressive Agents; Limit of Detection; Male; Middle Aged; Prednisolone; Tacrolimus; Vitamin D

The CYP3A metric 4β-hydroxycholesterol (4βOHC) has been shown to correlate with tacrolimus steady-state apparent oral clearance (CL/F). Recently, pretransplant 4βOHC was shown not to predict tacrolimus CL/F after transplantation in a cohort of renal recipients (n = 79). The goal of the current study was determine whether these findings could be validated in a substantially larger cohort.. In a retrospective analysis of 279 renal recipients, tacrolimus trough concentrations (C0), daily dose, haematocrit and other relevant covariates were registered every day for the first 14 days after transplantation. 4βOHC and cholesterol were quantified on plasma collected immediately pretransplant using liquid chromatography tandem-mass spectrometry. Patients were genotyped for CYP3A5*1 and CYP3A4*22.. The CYP3A metric 4βOHC cannot be used to predict tacrolimus dose requirements in the first days after transplantation.

Topics: Adult; Age Factors; Aged; Biological Variation, Population; Biomarkers, Pharmacological; Cytochrome P-450 CYP3A; Female; Genotype; Glomerular Filtration Rate; Graft Rejection; Hematocrit; Humans; Hydroxycholesterols; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Postoperative Period; Preoperative Period; Retrospective Studies; Tacrolimus