PKQuest: capillary permeability limitation and plasma protein binding – application to human inulin, dicloxacillin and ceftriaxone pharmacokinetics

BACKGROUND: It is generally assumed that the tissue exchange of antibiotics is flow limited (complete equilibration between the capillary and the tissue water). This assumption may not be valid if there is a large amount of plasma protein binding because the effective capillary permeability depends on the product of the intrinsic capillary permeability (PS) and the fraction of solute that is free in the blood (fw(B)). PKQuest, a new generic physiologically based pharmacokinetic software routine (PBPK), provides a novel approach to modeling capillary permeability in which the only adjustable parameter is the PS of muscle. METHODS: All the results were obtained by applying PKQuest to previously published human pharmacokinetic data. RESULTS: The PKQuest analysis suggests that the highly protein bound antibiotics dicloxacillin and ceftriaxone have a significant capillary permeability limitation. The human muscle capillary PS of inulin, dicloxacillin and ceftriaxone was 0.6, 13 and 6 ml/min/100 gm, respectively. The ceftriaxone protein binding is non-linear, saturating at high plasma concentrations. The experimental ceftriaxone data over a wide range of intravenous inputs (0.15 to 3 gms) was well described by PKQuest. PKQuest is the first PBPK that includes both permeability limitation and non-linear binding. CONCLUSIONS: Because of their high degree of plasma protein binding, dicloxacillin and ceftriaxone appear to have a diffusion limited exchange rate between the blood and tissue and are not flow limited as had been previously assumed. PKQuest and all the examples are freely available at

A histological and micro-CT investigation in to the effect of NGF and EGF on the periodontal, alveolar bone, root and pulpal healing of replanted molars in a rat model - a pilot study

Background: This study aims to investigate, utilising micro-computed tomography (micro-CT) and histology, whether the topical application of nerve growth factor (NGF) and/or epidermal growth factor (EGF) can enhance periodontal, alveolar bone, root and pulpal tissue regeneration while minimising the risk of pulpal necrosis, root resorption and ankylosis of replanted molars in a rat model. Methods: Twelve four-week-old male Sprague-Dawley rats were divided into four groups: sham, collagen, EGF and NGF. The maxillary right first molar was elevated and replanted with or without a collagen membrane impregnated with either the growth factors EGF or NGF, or a saline solution. Four weeks after replantation, the animals were sacrificed and the posterior maxilla was assessed using histological and micro-CT analysis. The maxillary left first molar served as the control for the corresponding right first molar. Results: Micro-CT analysis revealed a tendency for all replanted molars to have reduced root length, root volume, alveolar bone height and inter-radicular alveolar bone volume. It appears that the use of the collagen membrane had a negative effect while no positive effect was noted with the incorporation of EGF or NGF. Histologically, the incorporation of the collagen membrane was found to negatively affect pulpal, root, periodontal and alveolar bone healing with pulpal inflammation and hard tissue formation, extensive root resorption and alveolar bone fragmentation. The incorporation of EGF and NGF did not improve root, periodontal or alveolar bone healing. However, EGF was found to improve pulp vascularisation while NGF improved pulpal architecture and cell organisation, although not to the level of the control group.Conclusions: Results indicate a possible benefit on pulpal vascularisation and pulpal cell organisation following the incorporation of EGF and NGF, respectively, into the alveolar socket of replanted molars in the rat model. No potential benefit of EGF and NGF was detected in periodontal or root healing, while the use of a collagen membrane carrier was found to have a negative effect on the healing response