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The purpose of this study was to evaluate the similarity of dissolution and permeability properties of commercially available immediate-release metformin hydrochloride (MH) tablets (1000 mg strength) including five generic products obtained from the Turkish drug market (tablets A-E) and two reference products (obtained from the Turkish and European markets). In vitro dissolution studies were conducted in accordance with the MH tablet monograph in the USP (1000 mL, 75 rpm) and with the BCS-based biowaiver guidance in three different media (pH 1.2, pH 4.5, and pH 6.8; 900 mL, 50 rpm). The apparent permeability of MH in all tablets and raw MH was determined in Caco-2 cells. Dissolution studies revealed that neither the generics (except generic tablet B) nor the reference tablets fulfilled the criteria for very rapid dissolution. Although the dissolution profiles of the reference tablets were similar (f 2 > 50), none of the generic tablets were similar to either of the reference tablets. Permeability of MH for all reference and generic tablet formulations was similar to that of raw MH (p > 0.05). In contrast, a significant difference in permeability was observed between the two reference tablets (p < 0.05), and only one generic tablet (A) had permeability similar to both reference tablets. As MH has low permeability, potential alterations in permeability due to the dosage form can affect its bioavailability. The results of this study indicate that immediate-release MH tablets do not meet the criteria for very rapid dissolution for the BCS-based biowaiver.

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Transporter‐mediated drug–drug interactions are one of the major mechanisms in pharmacokinetic‐based drug interactions and correspondingly affecting drugs' safety and efficacy. Regulatory bodies underlined the importance of the evaluation of transporter‐mediated interactions as a part of the drug development process. The liver is responsible for the elimination of a wide range of endogenous and exogenous compounds via metabolism and biliary excretion. Therefore, hepatic uptake transporters, expressed on the sinusoidal membranes of hepatocytes, and efflux transporters mediating the transport from hepatocytes to the bile are determinant factors for pharmacokinetics of drugs, and hence, drug–drug interactions. In parallel with the growing research interest in this area, regulatory guidances have been updated with detailed assay models and criteria. According to well‐established preclinical results, observed or expected hepatic transporter‐mediated drug–drug interactions can be taken into account for clinical studies. In this paper, various methods including in vitro, in situ, in vivo, in silico approaches, and combinational concepts and several clinical studies on the assessment of transporter‐mediated drug–drug interactions were reviewed. Informative and effective evaluation by preclinical tools together with the integration of pharmacokinetic modeling and simulation can reduce unexpected clinical outcomes and enhance the success rate in drug development.

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