Biomedical subjects

Elisabeth Niel

Publications and source records attributed to Elisabeth Niel.

3 recordsLinked to original sources

PubMed2006

Colchicine today.

Colchicine is used chiefly in the treatment of gout but is also valuable in other inflammatory diseases such as familial Mediterranean fever (FMF). Three proteins play pivotal roles in colchicine pharmacokinetics: the colchicine receptor, tubulin, which governs the plasma elimination half-life of the drug; intestinal and hepatic CYP3A4, which is key to the biotransformation of colchicine; and P-glycoprotein, a cell efflux pump that regulates the tissue distribution of colchicine, as well as its excretion via the biliary tract and kidneys. Pharmacokinetic studies have been performed using a radioimmunology assay to measure blood colchicine levels. Absorption after oral ingestion varies widely (from 24% to 88% of the dose), the volume of distribution is extremely large (7 l/kg), and binding to albumin is moderate. Colchicine is excreted chiefly through the liver and has an elimination half-life of 20-40 hours. With repeated doses of about 1mg/day, the steady-state is achieved within 8 days and concentrations range from 0.3 to 2.5 ng/ml. Studies of associations between pharmacokinetic parameters and pharmacodynamics show that effects are correlated, not to plasma levels, but to levels in leukocytes. Adverse events are not uncommon, most notably when colchicine is used in combination with drugs that interact with CYP3A4 and/or P-glycoprotein, thereby decreasing the renal and/or hepatic elimination of colchicine. Careful monitoring in this situation is effective in preventing the development of toxicity.

Colchicine↗

PubMed2006

Is P-glycoprotein (ABCB1) a phase 0 or a phase 3 colchicine transporter depending on colchicine exposure conditions?

This study investigates the P-glycoprotein (Pgp)-mediated transport of its substrates in accumulation or efflux modes under steady-state conditions. The kinetics of colchicine uptake and efflux, a substrate of both Pgp and intracellular tubulin, were studied in HL60 and HL60/DNR cells; HL60/DNR cells contain 25 times more Pgp than do HL60 cells. HL60/DNR cells in a medium containing 6.25 nM colchicine, which mimics therapeutic conditions, reached steady-state twice as rapidly as did HL60 cells, and accumulated 24-times less colchicine than did HL60 cells. The Pgp inhibitor GF120918, increased colchicine uptake by HL60 cells 1.2-fold and that of HL60/DNR cells 17-fold, while it had no effect on colchicine efflux from either cell line that had been incubated with colchicine for 24 h. Colchicine kinetics fitted well a two closed-compartment model, showing that the low intracellular accumulation of colchicine in HL60/DNR cells resulted from a 11-fold decrease in colchicine uptake and a 2.3-fold increase in colchicine efflux, that could be attributed to Pgp-mediated efflux activity in HL60/DNR cells. Intracellular colchicine was mainly and similarly distributed in the cytosol in both cell lines. These data demonstrate that the kinetics of the intracellular colchicine accumulation depend on the density of Pgp and that Pgp is more a phase 0 (preventing cellular uptake) than a phase 3 (effluxing intracellular substrate) transporter under steady-state conditions, although the situation is reversed after a short incubation time (30 min), when intracellular free colchicine concentration is probably high enough for it to be removed from the cell by Pgp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Colchicine nonresponsiveness in familial Mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization.

OBJECTIVES: To identify the ethnic, clinical, genetic, and pharmacokinetic correlates of colchicine treatment failure in patients with familial Mediterranean fever (FMF). METHODS: Fifty-nine FMF patients, unresponsive to a daily dose of > or =2 mg colchicine, were compared with 51 colchicine-responsive patients by clinical, demographic, and socioeconomic assessment, FMF gene (MEditerranean FeVer [MEFV]) mutation and serum amyloid A1 (SAA1) gene polymorphism analysis, and plasma and white blood cell colchicine level determination. RESULTS: Colchicine responders and nonresponders were comparable with respect to gender, age, duration and onset of the disease, and various demographic parameters. The 2 cohorts were found to carry mainly the M694V MEFV mutation and had a similar number of homozygotes or compound heterozygotes. Predominance of the alpha/beta alleles of SAA1 and comparable plasma and polymorphonuclear colchicine concentrations characterized both groups. Nonresponders were from lower socioeconomic backgrounds, had less education, and a more severe form of disease. A statistically significant 2-fold elevation of colchicine concentration in the mononuclear cells (MNC) of responders was found. CONCLUSIONS: Colchicine treatment failure in FMF is associated with inadequate colchicine MNC concentration, probably resulting from a genetic defect unrelated to the underlying FMF.

Adult↗