Following oral administration, dabigatran etexilate (DABE) is rapidly hydrolyzed to its active form, dabigatran. DABE, but not dabigatran, presents as a P-glycoprotein (P-gp) substrate and has increasingly been used as a probe drug. Therefore, although dosed as DABE, a P-gp drug−drug interaction (DDI) is reported as a dabigatran plasma concentration ratio (perpetrator versus placebo). Because the majority of a DABE dose (80 to 85%) is recovered in urine as unchanged dabigatran (renal active secretion is ∼25% of total clearance), dabigatran was evaluated in vitro as a substrate of various human renal transporters. Active (pyrimethamine-sensitive) dabigatran uptake was observed with human embryonic kidney (HEK) 293 cells expressing multidrug and toxin extrusion protein 1 (MATE1) and 2K (MATE2K), with Michaelis−Menten constant (K m ) values of 4.0 and 8.0 μM, respectively. By comparison, no uptake of 2 μM dabigatran (versus mock-transfected HEK293 cells) was evident with HEK293 cells transfected with organic cation transporters (OCT1 and OCT2) and organic anion transporters (OAT1, 2, 3, and 4). The efflux ratios of dabigatran across P-gp-and BCRP (breast cancer resistance protein)-MDCK (Madin−Darby canine kidney) cell monolayers were 1.5 and 2.0 (versus mock-MDCK cell monolayers), suggesting dabigatran is a relatively poor P-gp and BCRP substrate. Three of five drugs (verapamil, ketoconazole, and quinidine) known to interact clinically with dabigatran, as P-gp inhibitors, presented as MATE inhibitors in vitro (IC 50 = 1.0 to 25.2 μM). Taken together, although no basolateral transporter was identified for dabigatran, the results suggest that apical MATE1 and MATE2K could play an important role in its renal clearance. MATEmediated renal secretion of dabigatran needs to be considered when interpreting the results of P-gp DDI studies following DABE administration.
Understanding the metabolism of newly developed drugs is paramount because of the central role metabolism plays in unraveling the possible toxicity or developability of new drug candidates. Therefore it is always important to understand the full set of metabolic reactions and enzymes involved in the metabolism of a compound in both preclinical models as well as in humans to avoid unnecessary complications or failures in drug development. Drug metabolism
in vivo
occurs everywhere within the body to differing extents, however metabolism occurs predominately in those organs involved in elimination and those to which the drug is first exposed.
In vitro
, there are multiple reagents that can be employed to evaluate metabolism or drug–drug interaction potential, such as microsomes, hepatocytes, and numerous subcellular fractions. The following text describes various
in vitro
and
in vivo
models often employed throughout drug discovery and development, as well as the purpose each model system serves to provide valuable information to elucidate the metabolic disposition of new drug molecules.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.