This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.

Background and purpose Late infections after total hip arthroplasty are still a problem. Treatment procedures include resection arthroplasty with implantation of antibiotic-loaded beads or implantation of an antibiotic-impreganted spacer. However, little is known about antibiotic elution from bone cement beyond the first 2–3 postoperative days in humans.Methods 17 hip spacers (80g PMMA, 1g gentamicin, and 4 g vancomycin) and 11 chains (40 g PMMA, 0.5 g gentamicin, and 2 g vancomycin) in 28 patients were studied. The release of both agents was measured in the drainage fluid on a daily basis. The drains were left in situ until less than 50 mL was produced per day. The elution of both antibiotics was determined by fluorescence polarization immunoassay. Systemic antibiotics were given postoperatively according to antibiogram. If possible, no gentamicin or vancomycin was given.Results Peak mean concentrations from beads and spacers were reached for gentamicin (1,160 (12–371) µg/mL and 21 (0.7–39) µg/mL, respectively) and for vancomycin (80 (21–198) µg/mL and 37 (3.3–72) µg/mL) on day 1. The last concentrations to be determined were 3.7 µg/mL gentamicin and 23 µg/mL vancomycin in the beads group after 13 days, and 1.9 µg/mL gentamicin and 6.6 µg/mL vancomycin in the spacer group after 7 days. Between the fifth and seventh day, an intermittent increase in elution of vancomycin from both beads and spacers and of gentamicin from spacers was noticed. No renal or hepatic dysfunction was observed.Interpretation Beads showed higher elution characteristics in vivo than the spacers due to their larger surface area; however, a great amount of inter-subject variability was seen for both beads and spacers. The inferior elution properties of spacers emphasize the importance of additional systemic antibiotics for this treatment procedure during the postoperative period. Future studies should clarify whether the dose of antibiotics or length of antibiotic therapy may be reduced in the case of bead implantation, without jeopardizing the control of infection.

The infection rate after primary hip arthroplasty lies at 1-2%. In the past few years, a two-stage protocol with the implantation of an antibiotic-loaded spacer has become a popular procedure in the treatment of infected hip joint arthroplasties. In this review, we pay special attention to the elution characteristics of the spacers, their mechanical stability and the clinical response. We conclude that hip spacers are an effective method in the treatment of hip joint infections, with success rates of over 90%.

Antibiotic-loaded acrylic bone cement is a well-established tool in the prophylaxis and treatment of orthopedic infections. Numerous studies about its pharmacokinetic properties have demonstrated that only a small part of the incorporated antibiotic amounts can be released, mostly over the first 8-10 weeks. Therefore, in the past 10 years, several attempts have been made for enhancement of the drug elution from bone cement. This article reviews this experience and pays special attention on biantibiotic combinations, additives other than antimicrobial agents, as well as the effect of ultrasound on the antibiotic elution characteristics.

No abstract