Pharmacokinetics, Pharmacodynamics and Dermal Distribution of 5-Methoxypsoralen Based on a Physiologically Based Pharmacokinetic Model to Support Phytotherapy Using Brosimum gaudichaudii

Abstract

The treatment of vitiligo includes the combination of psoralens and ultraviolet type A exposure. Psoralens belong to a group of natural furanocoumarins that cause the skin to become sensitive temporarily to ultraviolet type A. The aim of this study was to develop a physiologically based pharmacokinetic model of 5-MOP from Brosimum gaudichaudii to support psoralen and ultraviolet type A therapy. A study of rats was used to establish and validate rat tissue distribution. The same chemical-specific parameters used in the rat model were also employed in the human model to project human pharmacokinetics. The highest exposures in the rats were in the brain and skin. Following a single dose of 1.2 mg/kg 5-MOP in humans, the model predicted a maximum concentration of 20 ng/mL and an area under the curve of 125 ng.h/mL, matching clinical results. The half-maximum melanogenesis concentrations in B16F10 cells were 29.5, 18.5, 11.5, and 6.5 ng/mL for synthetic 5-MOP, synthetic 5-MOP with ultraviolet type A, B. gaudichaudii alone, and B. gaudichaudii plus ultraviolet type A, respectively. Physiologically based pharmacokinetic model prediction in humans supported a once-every-two-day regimen for optimal melanin production. This type of framework can be applied to support strategies for dose selection and to investigate the impact of drugs on melanocyte recovery.

Melanogenic Effect and Toxicity Assessments of Standardized Extract of Brosimum gaudichaudii

“…Those results were corroborated with our findings where we found that the maximum expression of melanin occurred at 48 h after the start of treatment (Martins et al 2020). The current study provides an insight into the therapeutic window of B. gaudichaudii extract.…”

Exploring Cheminformatic Toolsets for Predicting the Dermal Toxicity of Furanocoumarins

“…Moreover, this core moiety confers enough lipophilicity to these chemicals to allow their diffusion through the skin and cross other biological barriers such as the blood-brain barrier [56]. In this work, several databases provided similar physicochemical and pharmacokinetic information about LF (Table 1 and 2), being these data also supported by empiric research found in the literature [57][58][59][60]. Notwithstanding, the correlation of the findings through PCA showcased trends by other reports, such as the molecular weight, polar surface and Log P and Log Kp B eigenvectors convergence (Figure 1).…”

“…This difference may be attributed to distinct algorithms and weightings employed when imputed information was compiled [35,38,39]. Regardless of the case, Pred-Skin results were sound when compared to empiric investigations, which showcased the skin sensitizing effects of LF by different in vitro and in vivo approaches [1,3,59,60]. Care must be taken, however, because these results imply by no means that one database is more reliable than the other, considering the narrow scope of our investigation.…”

Physiologically based pharmacokinetic modelling to inform combination dosing regimens of ceftaroline and daptomycin in special populations

“…We surveyed paediatric dosing regimens used in bacteraemia due to VNS MRSA from case reports; the dosing regimens were higher than the recom- parameters should be between 0.5 and 2.0. 22,60 There is a lack of systematic analysis of appropriate dosing regimens for coadministration of antibiotics that also take into account the in vitro susceptibility information, even though β-lactam antibiotics combined with daptomycin against S. aureus has been consistently shown to produce in vitro synergistic activities. 45,[61][62][63][64] There are limitations in the current study.…”