Anatomical, physiological and metabolic changes with gestational age during normal pregnancy: A database for parameters required in physiologically based pharmacokinetic modelling

摘要

Background: Pregnancy is associated with considerable changes in the physiological, anatomical and biochemical attributes in women. These may alter the exposure to xenobiotics between pregnant and non-pregnant women who receive similar doses, with implications for different susceptibility to environmental pollutants or therapeutic agents. Physiologically based pharmacokinetic (PBPK) models together with invitro in vivoextrapolation (IVIVE) of absorption, distribution, metabolism and excretion (ADME) characteristics may capture the likely changes. However, such models require comprehensive information on the longitudinal variations of PBPK parameter values; a set of data that are as yet not available from a singular source. Aim: The aim of this article was to collect, integrate and analyse the available time-variant parameters that are needed for the PBPK modelling of xenobiotic kinetics in a healthy pregnant population. Methods: A structured literature search was carried out on anatomical, physiological and biochemical parameters likely to change in pregnancy and alter the kinetics of xenobiotics. Collated data were carefully assessed, integrated and analysed for trends with gestational age. Algorithms were generated to describe the changes in parameter values with gestational age. These included changes in maternal weight, the individual organ volumes and blood flows, glomerular filtration rates, and some drug-metabolising enzyme activities. Results: Articles were identified using relevant keywords, quality appraised and data were extracted by two investigators. Some parameters showed no change with gestational age and for others robust data were not available. However, for many parameters significant changes were reported during the course of pregnancy, e.g. cardiac output, protein binding and expression/activity of metabolizing enzymes. The trend for timevariant parameters was not consistent (with respect to direction and mono-tonicity). Hence, various mathematical algorithms were needed to describe individual parameter values. Conclusion: Despite the limitations identified in the availability of some values, the collected data presented in this paper provide a potentially useful singular resource for key parameters needed for PBPK modelling in pregnancy. This facilitates the risk assessment of environmental chemicals and therapeutic drug dose adjustments in the pregnant population.