(T1130-10-64) Explore Gender Differences in Perfluorooctanoic Acid Using Ontogeny Integrated Physiologically-Based Pharmacokinetic Model in Rats

Purpose: The in vivo kinetics of perfluorooctanoic acid (PFOA) was described through ontogeny in renal transporters, body weight, and albumin concentration combined physiologically-based pharmacokinetic (PBPK) model to explore the gender differences in rats.

Methods: An animal pharmacokinetic (PK) experiment was performed in male and female Sprague Dawley rats. The dose was 5 mg/kg via bolus intravenous administration. The PBPK model was developed in Berkely Madonna software (version 8.3.14), and for visualization, R software (version 4.2.2) with the ggplot package (version 3.4.1) was used. Ontogeny data were extracted from the literature and processed with non-linear regression in GraphPad Prism 5.

Results: Among the ontogeny factors, the renal transporters were key determinants for gender differences in the kinetic profile of PFOA. The Oat1, Oat3, and Oatp1a1 were integrated into the model with in vitro kinetic data and approximated proximal tubule cells per gram kidney (PTCPGK). The transport kinetics were modeled using the Michaelis-Menten equation, and the V_max (μg/hr/g kidney) and K_m (μg/L) were 11.74 and 51.0 for Oat1, 10.19 and 80.2 for Oat3, and 95.4 and 162.2 for Oatp1a1. The PTCPGK in rats was calculated as 687·10⁶ cells/g kidney in adult rats. The area under the plasma-time curve (μg·hr/mL) from model prediction and experimentation were 5425.0 and 4175.5 in male rats and 282.8 and 217.5 in female rats.

Conclusion: The results showed that the in vitro transporter kinetics of PFOA and ontogeny accounted for in vivo kinetics well. Furthermore, the model showed that the renal transporter is an important factor in gender differences in rats. Based on these results, it is expected that human prediction and risk assessment with high accuracy and precision will be possible by reflecting human ontogeny and physiology.

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Acknowledgements: This research was supported by a grant from the Ministry of Food and Drug Safety (21162MFDS077).

Figure 1. Ontogeny of physiological parameters of (A) body weight and (B) renal proximal epithelial cell transporters in rats

Figure 2. The plasma concentration of PFOA from PBPK model prediction (line) and observation (circles)