Pregnant women and their babies encounter many medications, including short term exposure to antibiotics or extended exposure to drugs for diabetes or epilepsy1. Pregnant women are not often recruited into clinical trials to test new and existing medicines, because of the risk of causing development abnormalities in the fetus and/or adverse side effects in the mother. Thus, there is a significant lack of information on the pharmacokinetics of many common drugs in pregnant women, which can lead to suboptimal dosing, reduced efficacy and/or increased risk of toxicity. In non-pregnant individuals, the liver is the major eliminating organ. However in pregnancy, drugs can also distribute in the placenta, where they can be metabolised and/or excreted by a variety of influx and efflux transporters and metabolising enzymes. These processes can influence drug concentration in maternal plasma, therapeutic effects and safety. Therefore, to accurately understand and predict drug action in pregnancy, the capacity of the placenta to transport and metabolise drugs must be investigated. Physiologically-based pharmacokinetic (PBPK) modelling is a translational tool widely used in drug development to improve drug safety in scenarios where clinical data are lacking2.
Metformin is prescribed in pregnancy for the management of type II and gestational diabetes; it is distributed from the plasma into the liver via the organic cation transporter-1 (OCT1), where it exerts its pharmacological effect. Metformin is not metabolised, and is excreted unchanged in the urine; renal clearance is mediated via OCT2 and MATE transporters3. The human placenta also expresses OCT and MATE transporters, and in the third trimester of pregnancy is perfused with 600-700 ml blood/minute; thus, the placenta also represents a significant site of drug distribution. Uptake of metformin by the placenta can therefore alter rates of uptake in the maternal liver, influencing concentrations in this target tissue and therefore therapeutic efficacy. Hence, the dosing regimen used in non-pregnant individuals may not be appropriate for pregnant women, and requirements may change throughout gestation, in line with placental growth.
The aim of this study is to collect robust biological and clinical data on placental OCT and MATE expression, and plasma metformin and glucose concentrations in diabetic pregnant women. These data will be incorporated into PBPK models, together with other known physiological parameters, to predict metformin pharmacokinetics and efficacy in pregnancy. Gaining a better understanding of drug actions and interactions in diabetic pregnancy will facilitate more effective clinical decision making, leading to improved clinical outcomes.
https://www.research.manchester.ac.uk/portal/lynda.k.harris.html
https://www.research.manchester.ac.uk/portal/aleksandra.galetin.html
https://www.research.manchester.ac.uk/portal/jenny.myers.html
https://www.research.manchester.ac.uk/portal/jill.barber.html
https://www.capkr.manchester.ac.uk/
Entry Requirements
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
How to Apply
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships
Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
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