Physiologically based modeling of p‐tert‐octylphenol kinetics following intravenous, oral or subcutaneous exposure in male and female Sprague–Dawley rats

Abstract

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for p-tert-octylphenol (OP) for understanding the qualitative and quantitative determinants of its kinetics in Sprague-Dawley rats. Compartments of the PBPK model included the liver, richly perfused tissues, poorly perfused tissues, reproductive tissues, adipose tissue and subcutaneous space, in which OP uptake was described as a blood flow- or a membrane diffusion-limited process. The PBPK model successfully simulated previously published data on blood and tissue OP concentrations in Sprague-Dawley rats following oral, intravenous (i.v.) or subcutaneous (s.c.) routes. The model predicted that OP concentrations would reach 6.8, 13.8 and 27.9 ng ml(-1) (male) and 7.2, 14.7 and 31.4 ng ml(-1) (female), 4 h after a single i.v. dose of 2, 4 and 8 mg kg(-1), respectively. The model also predicted that OP concentrations would reach 53.3, 134.8 and 271.2 ng ml(-1) (male) and 87.4, 221.4 and 449.7 ng ml(-1) (female) 4 h after a single oral dose (50, 125 and 250 mg kg(-1)) and that, 4 h after a single s.c. dose (125 mg kg(-1)), OP concentrations would reach 111.3 ng ml(-1) (male) and 121.6 ng ml(-1). A marked sex difference was seen in blood and tissue OP concentrations. This was reflected in the model by a gender-specific maximal velocity of metabolism (V(max)) that was higher (1.77 x) in male than in female rats. Further studies are required to elucidate the mechanism underlying the gender differences and to evaluate whether that is also observed in humans.

SubQ-Sim: A Subcutaneous Physiologically Based Biopharmaceutics Model. Part 1: The Injection and System Parameters

“…Typical values range between 3.8 [2.8–9.5] μL/h/g tissue for males to 4 [3–9.5] μL/h/g tissue for females. This IF flow is in agreement with measured values in the skin of rat and rabbit [ 4 – 6 ] μL/h/g [ 16 ]. This IF separates in lymph for 15% and the remaining volume 85% of the IF is reabsorbed by the venous capillaries within the tissue.…”

“…To achieve long-term oncology or HIV treatments, subcutaneous administration is increasingly utilized [ 1 – 3 ]. The absorption pathways for drugs from the SC space or adipose tissue (AT) have been described in the literature and some models have been proposed to predict the absorption rate from the subcutaneous space [ 4 – 6 ]. However, the impact of physiology, life events, administration site and disease have not been extensively covered.…”

Physicologically Based Toxicokinetic Models of Tebuconazole and Application in Human Risk Assessment

“…It is possible that it takes some time to establish equilibrium in a living system, although the data show surprisingly long lag times compared to those of other i.v. studies. − It should be mentioned that each data point is based on one animal only and that the oddity of this data point might also be caused by the genetic variability of one of the animals or other experimental problems. The flow-regulated well stirred model approach can be considered appropriate for all but the lowest time point.…”

Physiological-based pharmacokinetic modeling of endotoxin in the rat

“…Usually more advanced membrane-resistance or diffusion-limited models or even more complex transport models are used (Andersen and Dennison, 2001;Levitt, 2010;Lutz et al, 1980). These advanced models have been used for compounds such as tert-amyl alcohol (an oxygenated gasoline additive to reduce CO emissions in winter), a cyclosporine derivative immunosuppressant, p-tertoctylphenol (an ionic surfactant found in waste water), trichloroethylene (an industrial chemical in the environment), and dimethylarsinic acid (a herbicide; Albanese et al, 2002;Collins et al, 1999;Evans et al, 2008;Hamelin et al, 2010;Kawai et al, 1994).…”