Evaluation of the Potential Impact of Age- and Gender-Specific Pharmacokinetic Differences on Tissue Dosimetry 2Current address: Novartis Pharmaceuticals, East Hanover, NJ 07936.

TLDR

The physiological and biochemical processes that determine xenobiotic tissue concentration time courses vary with age and gender, and these differences can affect tissue concentrations and individual risk, but their relative importance and quantitative impact across life stages remain poorly characterized. The study aimed to identify age‑ and gender‑specific differences in physiological and biochemical processes affecting tissue dosimetry and incorporate them into a predictive physiologically based pharmacokinetic life‑stage model. The life‑stage model was applied to several environmental chemicals with diverse physicochemical, biochemical, and mode‑of‑action properties. Predicted average pharmacokinetic dose metrics across life stages were within a factor of two, with larger transient variations during the neonatal period; the most critical age‑dependent factor is reduced clearance in the perinatal period due to immature metabolic enzymes, which may also lower reactive metabolite production, and this transient decreased clearance could substantially impact risk for certain chemicals and health outcomes.

Abstract

The physiological and biochemical processes that determine the tissue concentration time courses (pharmacokinetics) of xenobiotics vary, in some cases significantly, with age and gender. While it is known that age- and gender-specific differences have the potential to affect tissue concentrations and, hence, individual risk, the relative importance of the contributing processes and the quantitative impact of these differences for various life stages are not well characterized. The objective of this study was to identify age- and gender-specific differences in physiological and biochemical processes that affect tissue dosimetry and integrate them into a predictive physiologically based pharmacokinetic (PBPK) life-stage model. The life-stage model was exercised for several environmental chemicals with a variety of physicochemical, biochemical, and mode-of-action properties. In general, predictions of average pharmacokinetic dose metrics for a chemical across life stages were within a factor of two, although larger transient variations were predicted, particularly during the neonatal period. The most important age-dependent pharmacokinetic factor appears to be the potential for decreased clearance of a toxic chemical in the perinatal period due to the immaturity of many metabolic enzyme systems, although this same factor may also reduce the production of a reactive metabolite. Given the potential for age-dependent pharmacodynamic factors during early life, there may be chemicals and health outcomes for which decreased clearance over a relatively brief period could have a substantial impact on risk.