Dataset Information

Metabolism and pharmacokinetics of vitamin D in patients with cystic fibrosis.

ABSTRACT: Patients with cystic fibrosis (CF) commonly have lower circulating concentrations of 25-hydroxyvitamin D (25(OH)D) than healthy populations. We comprehensively compared measures of vitamin D metabolism among individuals with CF and healthy control subjects. In a cross-sectional study, serum from participants with CF (N = 83) and frequency-matched healthy control subjects by age and race (N = 82) were analyzed for: 25(OH)D₂ and 25(OH)D₃, 1α,25-dihydroxyvitamins D₂ and D₃ (1α,25(OH)₂D₂ and 1α,25(OH)₂D₃), 24,25-dihydroxyvitamin D₃ (24,25(OH)₂D₃), 4β,25-dihydroxyvitamin D₃ (4β,25(OH)₂D₃), 25-hydroxyvitamin D₃-3-sulfate (25(OH)D₃-S), and 25-hydroxyvitamin D₃-3-glucuronide (25(OH)D₃-G). In a 56-day prospective pharmacokinetic study, ∼25 μg deuterium-labeled 25(OH)D₃ (d₆-25(OH)D₃) was administered intravenously to participants (N = 5 with CF, N = 5 control subjects). Serum was analyzed for d₆-25(OH)D₃ and d₆-24,25(OH)₂D₃, and pharmacokinetic parameters were estimated. In the cross-sectional study, participants with CF had similar mean (SD) total 25(OH)D concentrations as control subjects (26.7 [12.3] vs. 27.7 [9.9] ng/mL) and had higher vitamin D supplement use (53% vs. 22%). However, participants with CF had lower total 1α,25(OH)₂D (43.6 [12.7] vs. 50.7 [13.0] pg/mL), 4β,25(OH)₂D₃ (52.1 [38.9] vs. 79.9 [60.2] pg/mL), and 25(OH)D₃-S (17.7 [11.6] vs. 30.1 [12.3] ng/mL) (p < 0.001 for all). The pharmacokinetics of d₆-25(OH)D₃ and d₆-24,25(OH)D₃ did not differ between groups. In summary, although 25(OH)D concentrations were comparable, participants with CF had lower 1α,25(OH)₂D, 4β,25(OH)₂D₃, and 25(OH)D₃-S concentrations than healthy controls. Neither 25(OH)D₃ clearance, nor formation of 24,25(OH)₂D₃, appears to account for these differences and alternative mechanisms for low 25(OH)D in CF (i.e., decreased formation, altered enterohepatic recirculation) should be explored.

SUBMITTER: Bergagnini-Kolev MC

PROVIDER: S-EPMC10524963 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Metabolism and pharmacokinetics of vitamin D in patients with cystic fibrosis.

Bergagnini-Kolev Mackenzie C MC Hsu Simon S Aitken Moira L ML Goss Christopher H CH Hoofnagle Andrew N AN Zelnick Leila R LR Lum Dawn D Best Cora M CM Thummel Kenneth E KE Kestenbaum Bryan R BR de Boer Ian H IH Lin Yvonne S YS

The Journal of steroid biochemistry and molecular biology 20230520

Patients with cystic fibrosis (CF) commonly have lower circulating concentrations of 25-hydroxyvitamin D (25(OH)D) than healthy populations. We comprehensively compared measures of vitamin D metabolism among individuals with CF and healthy control subjects. In a cross-sectional study, serum from participants with CF (N = 83) and frequency-matched healthy control subjects by age and race (N = 82) were analyzed for: 25(OH)D2 and 25(OH)D3, 1α,25-dihydroxyvitamins D2 ...[more]

PMID: 37217104

Similar Datasets

Project description:Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg-1; CLNR, 0.59 ± 0.30 liters · h-1; CLθ, 5.97 × 10-3 ± 1.24 × 10-3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h-1 The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter-1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).

Project description:Cystic fibrosis (CF) is an inherited syndrome associated with a mutation in a cystic fibrosis transmembrane conductance regulator gene, composed of exocrine gland dysfunction involving multiple systems that may result in chronic respiratory infections, pancreatic enzyme deficiency, and developmental disorders. Our study describes for the first time the urinary profile of glucocorticoid metabolites and the activity of the enzymes involved in the development and metabolism of cortisol in patients with CF, using a gas chromatography/mass spectrometry method. Data were obtained from 25 affected patients and 70 sex- and age- matched healthy volunteers. We have shown a general decrease in the activity of enzymes involved in the peripheral metabolism of cortisol, such as 11β-hydroxysteroid dehydrogenase type 2, 5α- and 5β-reductases. In contrast, the activity of 11β-hydroxysteroid dehydrogenase type 1, the enzyme that converts cortisone to cortisol, increased. Furthermore, our study found a significant decrease in glucocorticoid excretion in patients with CF. This may suggest adrenal insufficiency or dysregulation of the HPA axis and the development of peripheral mechanisms to counteract cortisol degradation in the case of reduced synthesis of glucocorticoids by the adrenal glands. Furthermore, the activity of 5α-reductase seems to be enhanced only through the backdoor pathway, especially when we taking into consideration 11β-hydroxyandrosterone/11β-hydroxyetiocholanolone ratio which has been shown to be the best differential marker for enzyme activity. CF impairs nutritional effects and energetic balance in patients; thus, our findings suggest the existence of adaptive mechanisms due to limited secretion of adrenal steroids and subsequent diminished amounts of their metabolites in urine. On the other hand, local control of cortisol availability is maintained by enhanced 11βHSD1 activity and its recovery from cortisone in organs and tissues which need this. Steroid hormone dysregulation might be another important factor in the course of CF that should be taken into account when planning an effective and comprehensive therapy.

Dataset Information

Metabolism and pharmacokinetics of vitamin D in patients with cystic fibrosis.

Publications

Metabolism and pharmacokinetics of vitamin D in patients with cystic fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets