Fractional dynamics pharmacokinetics–pharmacodynamic models

While an increasing number of fractional order integrals and differential equations applications have been reported in the physics, signal processing, engineering and bioengineering literatures, little attention has been paid to this class of models in the pharmacokinetics–pharmacodynamic (PKPD) literature. One of the reasons is computational: while the analytical solution of fractional differential equations is available in special cases, it this turns out that even the simplest PKPD models that can be constructed using fractional calculus do not allow an analytical solution. In this paper, we first introduce new families of PKPD models incorporating fractional order integrals and differential equations, and, second, exemplify and investigate their qualitative behavior. The families represent extensions of frequently used PK link and PD direct and indirect action models, using the tools of fractional calculus. In addition the PD models can be a function of a variable, the active drug, which can smoothly transition from concentration to exposure, to hyper-exposure, according to a fractional integral transformation. To investigate the behavior of the models we propose, we implement numerical algorithms for fractional integration and for the numerical solution of a system of fractional differential equations. For simplicity, in our investigation we concentrate on the pharmacodynamic side of the models, assuming standard (integer order) pharmacokinetics

Expression of ABC Efflux Transporters in Placenta from Women with Insulin-Managed Diabetes

Drug efflux transporters in the placenta can significantly influence the materno-fetal transfer of a diverse array of drugs and other xenobiotics. To determine if clinically important drug efflux transporter expression is altered in pregnancies complicated by gestational diabetes mellitus (GDM-I) or type 1 diabetes mellitus (T1DM-I), we compared the expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2) and the breast cancer resistance protein (BCRP) via western blotting and quantitative real-time polymerase chain reaction in samples obtained from insulin-managed diabetic pregnancies to healthy term-matched controls. At the level of mRNA, we found significantly increased expression of MDR1 in the GDM-I group compared to both the T1DM-I (p<0.01) and control groups (p<0.05). Significant changes in the placental protein expression of MDR1, MRP2, and BCRP were not detected (p>0.05). Interestingly, there was a significant, positive correlation observed between plasma hemoglobin A1c levels (a retrospective marker of glycemic control) and both BCRP protein expression (r = 0.45, p<0.05) and BCRP mRNA expression (r = 0.58, p<0.01) in the insulin-managed DM groups. Collectively, the data suggest that the expression of placental efflux transporters is not altered in pregnancies complicated by diabetes when hyperglycemia is managed; however, given the relationship between BCRP expression and plasma hemoglobin A1c levels it is plausible that their expression could change in poorly managed diabetes

Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile

© 2016 The Author(s)The application of primary human hepatocytes following isolation from human tissue is well accepted to be compromised by the process of dedifferentiation. This phenomenon reduces many unique hepatocyte functions, limiting their use in drug disposition and toxicity assessment. The aetiology of dedifferentiation has not been well defined, and further understanding of the process would allow the development of novel strategies for sustaining the hepatocyte phenotype in culture or for improving protocols for maturation of hepatocytes generated from stem cells. We have therefore carried out the first proteomic comparison of primary human hepatocyte differentiation. Cells were cultured for 0, 24, 72 and 168 h as a monolayer in order to permit unrestricted hepatocyte dedifferentiation, so as to reveal the causative signalling pathways and factors in this process, by pathway analysis. A total of 3430 proteins were identified with a false detection rate of <1 %, of which 1117 were quantified at every time point. Increasing numbers of significantly differentially expressed proteins compared with the freshly isolated cells were observed at 24 h (40 proteins), 72 h (118 proteins) and 168 h (272 proteins) (p < 0.05). In particular, cytochromes P450 and mitochondrial proteins underwent major changes, confirmed by functional studies and investigated by pathway analysis. We report the key factors and pathways which underlie the loss of hepatic phenotype in vitro, particularly those driving the large-scale and selective remodelling of the mitochondrial and metabolic proteomes. In summary, these findings expand the current understanding of dedifferentiation should facilitate further development of simple and complex hepatic culture systems