Application of microdialysis to the pharmacokinetics of analgesics: problems with reduction of dialysis efficiency in vivo.

Microdialysis in freely moving rats coupled to high-performance liquid chromatography (HPLC) was used to measure the free concentration of acetaminophen (APAP) in blood and cerebrospinal fluid (CSF) after an intravenous bolus dose (25 mg/kg). In vitro calibration of two commercially available probe types was performed in 0.9% NaCl solution and blood. The influence of these media on recovery was tested by retrodialysis. This technique was also used for in vivo calibration and to monitor the dynamics of the performance of implanted probes. The results were compared with data obtained from conventional sampling techniques of direct withdrawal of blood and CSF, and also with the results obtained by correcting dialysate concentrations using in vitro recovery values. The data demonstrate that whole blood lowers recovery not only by reducing the free concentration of drug, but also by directly influencing dialysis efficiency (mean reduction of recovery: 50.1%). By contrast, low transport capacities of CSF surrounding the implanted probe lead to suboptimal conditions and, therefore, to a reduction of in vivo recovery (mean reduction of recovery: 65.5%). After correction of recovery values using in vivo retrodialysis prior to dosing the animal, we obtained similar data as compared to conventional sampling techniques. These results demonstrate that microdialysis may provide a minimally invasive method to monitor the free concentrations of drugs, such as acetaminophen, in different compartments, and allow a multitude of pharmacokinetic data to be obtained from freely moving animals.

Is the inversion from R- to S-ketoprofen concentration dependent? Investigations in rats in vivo and in vitro.

The effects of dose on the pharmacokinetics of ketoprofen (KT) enantiomers were investigated in rats in vivo and in hepatoma cells in continuous culture in vitro following administration of the optically pure enantiomers and the racemate of KT. With the exception of AUC (area under the curve) no pharmacokinetic differences could be found following i.v. administration of various doses of KT enantiomers (2.5, 5 and 10 mg/kg) and of racemic KT (5, 10 and 20 mg/kg) and between single enantiomer and racemate administration in rats in vivo. Independent of the dose administered the fraction inverted was about 66%. In line with the findings in vivo good correlation between incubation concentration and AUC of R- and S-KT was found in the hepatoma cells in vitro. The ratios of AUC(S)/AUC(R) were not significantly affected by concentration after R-KT (2.5-20 micrograms/mL) and racemate incubation (5-40 micrograms/mL) in the concentration ranges investigated. However, unlike in rats in vivo enhanced inversion was observed following racemate as compared to single enantiomer incubation in vitro.