Effect of the Plasticizer DEHP in Blood Collection Bags on Human Plasma Fraction Unbound Determination for Alpha-1-Acid Glycoprotein (AAG) Binding Drugs
The AAPS journal(2018)
Abstract
Fraction unbound (f u ) is a critical drug distribution parameter commonly utilized for modeling efficacious dosage and safety margin predictions. An over-estimation of f u for 13 chemically diverse small molecule drugs primarily bound to alpha-1-acid glycoprotein (AAG) in human plasma was discovered when in vitro results from our screening lab were compared to literature values. Di-(2-ethylhexyl) phthalate (DEHP), a plasticizer known to be used in the manufacture of blood collection bags, was extracted from plasma obtained through three common techniques that allowed contact with DEHP, and drug f u values in plasma from each collection method were estimated using the HTDialysis protein binding methodology. Additionally, f u of test compounds in plasma spiked with varying concentrations of DEHP (0–800 μM) was determined, and DEHP extractions were performed from plasma stored in Terumo bags over 7 days. Blood stored in Terumo bags, blood collected in Terumo bags, but immediately transferred to conical vials, and vacutainer-collected blood yielded DEHP concentrations of 300–1000 μM, 1–10 μM, and 0.1–2 μM, respectively. This finding corresponded with the f u of tested drugs in DEHP-spiked plasma increasing between 2- and 5-fold. Additionally, DEHP was discovered to leach from the Terumo bag, with concentrations increasing 10-fold over a 7-day test period. In summary, the presence of DEHP in commercially available blood collection bags confounds in vitro f u estimation for drugs that bind primarily to AAG. It is recommended that vacutainer-collected human plasma, which contains negligible DEHP, be used for the most accurate estimation of f u in human plasma.
MoreTranslated text
Key words
alpha-1-acid glycoprotein,equilibrium dialysis,plasma protein binding,plasticizer,di-(2-ethylhexyl) phthalate (DEHP)
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined