In Vitro Bioavailability of the Hydrocarbon Fractions of Dimethyl Sulfoxide (DMSO) Extracts of Petroleum Substances.

Determining the in vitro bioavailable concentration is a critical, yet unmet need to refine the in vitro-to-in vivo extrapolation (IVIVE) for Unknown or Variable composition, Complex reaction products or Biological materials (UVCBs) substances. UVCBs such as petroleum substances are subject to dimethyl sulfoxide (DMSO) extraction, in order to retrieve the bioactive polycyclic aromatic compounds (PAC) portion for in vitro testing. In addition to DMSO extraction, protein binding in cell culture media and dilution could all influence in vitro bioavailable concentrations of aliphatic and aromatic compounds in petroleum substances. However, effects of these in vitro factors have not been fully characterized. In this study, we aimed to fill in these data gaps by characterizing the effects of these processes using both a defined mixture of analytical standards containing aliphatic and aromatic hydrocarbons, as well as four refined petroleum products as prototypical examples of UVCBs. Each substance was extracted with DMSO, and the protein binding in cell culture media was measured by using solid-phase microextraction. Semi-quantitative analysis for aliphatic and aromatic compounds was achieved via gas chromatography mass spectrometry. Our results showed that DMSO selectively extracted PAC from test substances, and that chemical profiles of PAC across molecular classes remained consistent after extraction. With respect to protein binding, chemical profiles were retained at a lower dilution (higher concentration), but a greater dilution factor (i.e., lower concentration) resulted in higher protein binding in cell medium, which in turn altered the ultimate chemical profile of bioavailable PAC. Overall, this case study demonstrates that extraction procedures, protein binding in cell culture media, and dilution factors prior to in vitro testing can all contribute to determining the final bioavailable concentrations of bioactive constituents of UVCBs in vitro. Thus, IVIVE for UVCBs may require greater attention to the concentration-dependent and compound-specific differences in recovery and bioavailability.

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