Optimized blood sampling with cytidine deaminase inhibitor for improved analysis of capecitabine metabolites.

The 5FU prodrug capecitabine undergoes a 3-step enzymatic conversion, including the conversion of 5'DFRC into 5'DFUR by cytidine deaminase (CDA). The presence of CDA activity in blood led us to analyze the possible ex vivo conversion of 5'DFCR into 5'DFUR in blood samples. We thus examined the impact of the addition of a CDA inhibitor (tetrahydrouridine (THU) 1 microM final) in blood. Blood samples from 3 healthy volunteers were taken on tubes containing or not THU. Blood was spiked with 5'DFCR (20 microM final) (T0) and was maintained at room temperature for 2 h. Plasma concentrations of 5'DFRC and 5'DFUR were analyzed with an optimized HPLC assay. In the absence of THU, 5'DFUR was detectable as early as T0. The percent of 5'DFUR produced relative to 5'DFCR increased over time, up to 7.7 % at 2h. In contrast, the presence of THU totally prevents the formation of 5'DFUR. The impact of THU for preventing the conversion of 5'DFCR was confirmed by the analysis of blood samples from 2 capecitabine-treated patients. Addition of THU in the sampling-tube before the introduction of blood is thus strongly recommended in order to guarantee accurate conditions for reliable measurement of capecitabine metabolites in plasma, and thus faithful pharmacokinetic data.

Chronopharmacokinetics of imipenem in the rat.

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10:00, 16:00, 22:00, or 04:00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were C(max), T(max), elimination half-life (t(1/2)), area under the concentration-versus-time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of C(max) (49%), T(max) (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra-individual variability.

Supporting the One-Carbon Cycle Restores Ovarian Reserve in Subfertile Women: Absence of Correlation with Urinary Bisphenol A Concentration.

Environmental endocrine disrupting chemicals (EDCs), including bisphenol A (BPA), induce DNA methylation errors and oxidative stress, and alter fertility. Animal studies have demonstrated that supporting the one-carbon cycle (1-CC) with appropriate dietary supplements can reduce the effects of EDCs. Anti-Mullerian hormone (AMH), a marker of ovarian functionality, has been tested in subfertile female patients, to control this hypothesis in humans. Fifty-five women with a history of 3-7 years of infertility, with at least two assisted reproductive technology (ART) treatment failures, and low serum levels of AMH were enrolled in the study. Before starting any further ART treatment, they were tested for AMH and for follicular count. A urinary control of BPA was proposed. Then a support of the 1-CC, already tested in other clinical studies, was initiated and continued for 4 months. At the end of this period, antral follicle count and serum AMH levels were re-evaluated. The AMH levels before and after treatment were compared using the Wilcoxon test (nonparametric test, non-Gaussian population). Out of the 55 patients, 35 accepted a BPA dosage in the urine. No correlation was found between BPA and serum AMH concentrations. Forty-nine patients followed the full treatment with 1-CC supplements, which resulted in increased AMH levels, independent of initial AMH levels and maternal age (in the range studied), p = 0.0001. Eight patients spontaneously conceived ongoing pregnancies within 3 months, at the end of the protocol. A support of the 1-CC can partly alleviate metabolic derangements induced by environment, as observed in animal models, and improve endocrine background in women.