Journal
AAPS JOURNAL
Volume 21, Issue 1, Pages -Publisher
SPRINGER
DOI: 10.1208/s12248-018-0276-8
Keywords
alpha-1-acid glycoprotein; equilibrium dialysis; plasma protein binding; plasticizer; di-(2-ethylhexyl) phthalate (DEHP)
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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 (0-800M) was determined, and DEHP extractions were performed from plasma stored in Terumo bags over 7days. Blood stored in Terumo bags, blood collected in Terumo bags, but immediately transferred to conical vials, and vacutainer-collected blood yielded DEHP concentrations of 300-1000M, 1-10M, and 0.1-2M, 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.
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