New approach for accurate simulation of human pharmacokinetics in an in vitro pharmacodynamic model: application to ciprofloxacin.

An in vitro pharmacodynamic model using a disposable dialyser unit and computer-controlled devices was developed. Feedback control of peristaltic pump flow rates is used to maintain constant flow rates, thus avoiding the problem of the modification of the physical properties of the tubing that generally occurs. Fast equilibrium is obtained with capillaries, which allows simulation of the same kinetic profile in the central and the peripheral compartments. Thus, more accurate simulation of plasma, extracapillary fluid or whole tissue kinetics can be performed. Our model was validated by simulation of a 30 min infusion of a 200 mg dose, and of an oral administration of a 500 mg dose of ciprofloxacin.

Melatonin secretion occurs at a constant rate in both young and older men and women.

The magnitude and duration of melatonin (MLT) secretion were measured over a period of 25 h with pharmacokinetic studies employing administration of D(7) MLT at midday and at midnight in two separate studies and two groups of subjects, 12 young and 11 older men and women. Plasma levels of endogenous MLT and D(7) MLT were quantified separately by use of a specific and sensitive method (gas chromatography-mass spectrometry) previously developed in our laboratory, enabling us to measure endogenous and exogenous MLT levels down to 0.5 pg/ml in plasma. In the two groups of subjects, MLT secretion occurred only at night: onset time of secretion was from 1915 to 2205 (Greenwich mean time), and offset was from 0305 to 0545. No MLT peak was observed in individual nocturnal MLT profiles that were similar to curves obtained for a rate-constant infusion. Modelization demonstrated the superimposition of observed data and simulated curves. MLT concentrations decreasing from the offset of secretion might correspond to the elimination of MLT present in the body at the end of nocturnal secretion. By use of the MLT clearance given by pharmacokinetics, the amount of secreted MLT was found to be 35.7 and 21.6 microg for men and women, respectively, and the rate of secretion was 4.6 and 2.8 microg/h, respectively. No significant gender difference was observed for these two parameters when normalized to body weight. No significant gender difference was observed for onset times of secretion or duration of secretion (7.6-8.6 h) within the two groups, or between young and older subjects.

Fully automated high-performance liquid chromatography of ciprofloxacin with direct injection of plasma and Mueller-Hinton broth for pharmacokinetic/pharmacodynamic studies.

An isocratic high-performance liquid chromatographic method with column switching and direct injection has been developed to determine ciprofloxacin in plasma and Mueller-Hinton broth. An on-line dilution of the sample was performed with a loading mobile phase consisting of 173 mM phosphoric acid. The analyte was retained on a LiChrocart 4-4 precolumn filled with a LiChrospher 100 RP18, 5 microm. An electric-actuated system with two six-port valves allowed a clean-up step with a mixture 20 mM phosphate buffer (pH 3.5)-methanol (97:3, v/v) and the transfer of the analyte by a back-flush mode to a 150 x 4.6 mm I.D. column packed with a Kromasil C8 5 microm, using a mobile phase of 20 mM phosphate buffer (pH 3.5)-acetonitrile (85:15, v/v). Fluorescence detection allowed a quantification limit of 0.078 microg/ml with a 40-microl sample size. The method was evaluated to determine its usefulness in studying the pharmacokinetic/pharmacodynamic behaviour of ciprofloxacin in an in vitro model.