Membrane transporters play a significant role in the transport of many endogenous and exogenous compounds. The knowledge of transporter substrate requirements has allowed further development of drugs that utilize them to ensure tissue permeation. In this study, we demonstrate that inclusion of a biguanide functionality can potentiate uptake by the organic cation transporters 1 and 2 (OCT1 and OCT2). We synthesized 18 pairs of structurally diverse compounds, each pair consisting of a parent amino compound and its biguanide analog; and then assessed their cellular uptake in HEK293 cells overexpressing human OCT1 or OCT2. Our results show that addition of the biguanide significantly improved OCT1- and OCT2-mediated transport for the majority of compounds. The biguanides also inhibited the uptake of prototypical substrates of both transporters, 1-methyl-4-phenylpyridinium (MPP) and metformin. We found that molecular weight, molecular volume, Log D (pH 7.4), and accessible surface area were important determinants of OCT2 substrates, but none of these parameters was a significant factor for OCT1. More so, the inhibition of MPP uptake correlated linearly with that of metformin uptake for the tested biguanides in both cell lines. Taken together, we conclude that the inclusion of the biguanide scaffold in nonsubstrates of OCT1 and OCT2 increase their propensity to become substrates and inhibitors for these transporters.

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IMPACT: As the number of poorly water-soluble drugs in development increases, our research will expand on the science behind improving drug solubility and absorption and ensuring that promising poorly-water solubility drugs do not fail drug development. OBJECTIVES/GOALS: Spray-dried dispersion (SDD) tablet formulation is an approach to increase oral drug solubility and absorption. Methods to predict SDD performance in humans are poorly developed. We aim to develop an in vivo in vitro correlation (IVIVC) between in vitro dissolution and in vivo absorption of itraconazole SDD tablets. METHODS/STUDY POPULATION: This research project involves tablet manufacturing, in vitro dissolution experiments, and a clinical study. We manufactured fast-, medium-, and slowrelease SDD tablets containing amorphous solid dispersion of itraconazole (100 mg) and different grades of the polymer hypromellose acetate succinate (HPMC-AS). Tablets differed in slug pressure, tablet compression force, and formulation composition. Dissolution studies were performed using the United States Pharmacopeia (USP) type II apparatus. The clinical study is an ongoing randomized, cross-over, open-label, fasted, single-dose trial in healthy participants

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The coupling of aryl iodides with lactams (I) tolerates various functional groups in both partners to give N‐arylated products in good yields.