Georges Houin

Microdialysis probes calibration: Gradient and tissue dependent changes in No Net Flux and reverse dialysis methods

Probe calibrations are required for accurate estimations of extracellular concentrations in microdialysis experiments. Several methods have been developed and validated for in vivo determination of dialysis membrane recovery such as the perfusion rate method and the No Net Flux method. In this study, the No Net Flux and the reverse dialysis methods were investigated. Both measure the net transport of drug across the dialysis membrane. The recovery was defined as R = (Cin - Cout)/Cin, where Cin and Cout were the concentrations of a compound in the perfusate and in the dialysate, respectively. First, the accuracy of the No Net Flux method to estimate in vivo recovery was compared in two situations: diffusion from the probe into the dialysis medium and diffusion from the outer medium into the probe. The point of no net transport was used to estimate the concentration surrounding the probe. Neither difference between extracellular concentrations (intercept values) nor difference between recoveries were observed. Then the reverse dialysis method was tested to estimate the relative loss of drug from the perfusate when the probe was placed in a drug-free medium. Finally comparisons of the behavior of the drug diffusion across the membrane under increasing gradient conditions have shown an asymptotic profile, specific of the tissue; blood, muscle, and adipose tissue. The faster a drug was removed by microvascular transport (blood > muscle > adipocytes), the higher was the recovery, until the perfusate concentration reached a threshold value where the transport process became gradient limited and no more tissue limited.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of weightlessness on pharmacokinetics.

The primary hostile factor during a spaceflight is the lack of gravity, which can induce space motion sickness and act on bones, muscles and the cardiovascular system. These physiological effects may modify the pharmacokinetics of the drugs administered during the flight producing reduced pharmacological activity or appearance of adverse effects. Given the small number of spaceflights and the difficulties of conducting experiments during missions, pharmacokinetic data obtained in flight are insufficient to determine if drug monitoring is necessary for the drugs present in the onboard medical kit. Therefore, validated earthbound models like tail‐suspension performed with animals and long‐term bedrest performed with human volunteers are used to simulate weightlessness and to study the pharmacokinetic variations of either absorption, distribution, or elimination of drugs. As a result of these studies, it is possible to make some dosing recommendations but more information is necessary to predict with precision all of the pharmacokinetic variations occurring in spaceflight. To collect more pharmacokinetic information, head‐down bedrest studies are still the best solution and as saliva is an appropriate substitution for plasma for some drugs, salivary sampling can be planned during flights.

A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin : a step towards predicting bacterial killing at sites of infection.

The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic–pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration–time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin’s indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK–PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics .

Pharmacokinetics of low molecular weight dermatan sulphate (desmin) in different cohorts of patients.

BRIEF COMMUNICATION Pharmacokinetics of Low Molecular Weight Dermatan Sulphate (Desmin) in Different Cohorts of Patients Sylvie Saivin, Didier Carrie, Jean Escourrou, Patrick Duchene, Villiam Zamboni5, Miriam Barbanti5, Ernesto Palazzini5 and Georges Houin1 1Laboratoire de Pharmacocinetique et Toxicologie Clinique, Hopital Rangueil, Toulouse, France; Service de Cardiologie, Hopital Purpan, Toulouse, France; Service de Gastro-Enterologie et Nutrition, Hopital Rangueil, Toulouse, France; 4ADME Bioanalyses, Mougins, France; 5Alfa Wassermann, Bologna, Italy.