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Highly protein bound drugs behave differently in human serum than predicted from studies in protein free media in GD 13 rat embryos in vitro
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2013 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Although much reproductive toxicology research is performed in live animals there is increasing use of in vitro techniques. In vitro studies are usually undertaken using protein free media. Theoretically the effects in human serum can be predicted based on the calculated amount of free drug. The aim of the present study was to test this hypothesis on a range of drugs by comparing their effect on the heart rate of gestational day 13 rat embryos cultured in either a protein free media or in human sera. Eight drugs were tested; 3 antidepressants (citalopram, paroxetine, trazodone), 2 antiarrhythmics (amiodarone, dofetilide) and 3 antipsychotics (quetiapine, haloperidol, nortriptyline).

Seven of the eight tested drugs caused a concentration-dependent slowing of the embryonic heart when tested in protein free media. When the same concentrations were tested in human serum the heart rate reductions were much greater than predicted based on the protein binding of each drug.

The higher than predicted activity in human serum was possibly related to non-linear protein binding and lipophilicity (log P). Since lipophilic drugs are more likely to accumulate in tissues this property may be more important than drug binding in this system. However, it was not possible to assign any specific explanation to any one drug. Since the results did not confirm the original hypothesis, reproductive toxicity results obtained using protein free in vitro techniques may not have the large safety factors predicted on the basis of protein binding.

Place, publisher, year, edition, pages
2013. , 33 p.
Keyword [en]
Whole Rat Embryo Cuture, Human Serum
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:uu:diva-201119OAI: oai:DiVA.org:uu-201119DiVA: diva2:626049
External cooperation
University of Sydney (Bill Webster)
Subject / course
Educational program
Master of Science Programme in Pharmacy
2013-05-28, Sydney, 16:32 (English)
Available from: 2013-06-11 Created: 2013-06-06 Last updated: 2013-06-11Bibliographically approved

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