The untargeted nature of metabolomics allows measurement of biofluid chemistry related to both endogenous metabolism and host-environment exposures. Comprehensive coverage of chemically diverse constituents of human blood products benefits from the use of multiple methods, each oriented toward metabolite subsets generally segregated by polarity and hydrophobicity. Whilst recent developments in UHPLC-MS profiling methodologies have delivered numerous solutions for the analysis of polar molecules (e.g., via HILIC-MS) and complex lipids, the analysis of moderately hydrophobic and amphipathic molecules in plasma and serum by RPC methodology is complicated by the suppressive effects of lipids on the ionization of LMWMs. SPE techniques offer a solution to remove lipophilic species, but can often be expensive, affect recoveries of the other small molecules and introduce contamination. This study offers a solution for one of the major remaining gaps in endto-end comprehensive metabolome coverage. The proposed high-throughput and reproducible dSPE sample preparation technique provides a way to efficiently remove highly lipophilic species from the sample, but with minimal effect on moderately hydrophobic, amphipathic and polar LMWMs.