Effects of tetraalkylammonium compounds with different affinities for organic cation transporters on the pharmacokinetics of metformin

Abstract

The study sought to investigate the effects of tetraalkylammonium (TAA), inhibitors of the organic cation transporters (OCTs) with different affinities, on the pharmacokinetics of metformin. The inhibitory potentials of TAAs on the uptake of metformin were evaluated by determining IC(50) values in MDCK cells over-expressing OCTs and, to assess in vivo drug interactions, metformin and TAAs were coadministered to rats. Uptake of metformin was facilitated by over-expression of hOCT1 and hOCT2 and showed saturable processes, indicating that metformin is a substrate of hOCT1 and hOCT2. The IC(50) values of TAAs for hOCT2 were lower than hOCT1 and decreased with increasing alkyl chain length, indicating that the inhibitory potential of TAAs on metformin uptake was greater in hOCT2 than in hOCT1 and increased with increasing alkyl chain length. The plasma concentration of metformin was elevated by the coadministration of tetrapropylammonium (TPrA) and tetrapentylammonium (TPeA), but not by tetramethylammonium (TMA) or tetraethylammonium (TEA). However, the plasma concentrations of TMA, TEA and TPrA were not changed by the coadministration of metformin. In conclusion, in vivo drug interactions between metformin and TAAs were caused only when metformin was coadministered with TAAs showing higher affinities for OCTs.

Characterization of the Inhibitory Effects ofN-Butylpyridinium Chloride and Structurally Related Ionic Liquids on Organic Cation Transporters 1/2 and Human Toxic Extrusion Transporters 1/2-K In Vitro and In Vivo

“…The IC 50 values decreased significantly with an increase in the number of carbons on the alkyl chain. This SAR has also been reported for other chemical classes (Ullrich, 1997;Bednarczyk et al, 2003;Suhre et al, 2005;Choi et al, 2007). It was suggested that the hydrophobicity of the ILs increased with increasing alkyl chain length (Ranke et al, 2007).…”

“…When metformin, the widely prescribed type 2 antidiabetic drug, was used as the probe substrate for hOCT2, these ILs demonstrated even stronger inhibitory effects. This observation was also noted when tetraalkylammonium compounds were used to inhibit hOCT2-mediated MPP and metformin transport; i.e., transport of metformin was inhibited to a greater degree (Dresser et al, 2002;Choi et al, 2007). The reason for the different inhibitory effects observed for the two probe substrates is still not clear.…”

Pharmacokinetics and Hepatic Uptake of Eltrombopag, a Novel Platelet-Increasing Agent

“…5, A and B). TPeA has previously been used as an OCT inhibitor for in vivo studies (Choi et al, 2007). When ELT (1 mg/kg) was injected into mice, the maximal plasma concentration of ELT was at most 40 M (data not shown), and at this concentration, hepatic uptake of ELT was almost linear (Fig.…”

“…After 120 s, the mice were sacrificed, and liver and kidney were collected. In combination experiments with TPeA and RIF, TPeA and RIF were also injected via the jugular vein at doses of 30 mol/kg and 20 mg/kg, respectively, according to previous reports (Lau et al, 2006;Choi et al, 2007) at 1 and 5 min, respectively, before the administration of ELT.…”

A PET Tracer for Renal Organic Cation Transporters, 11C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies

“…Cimetidine (27,28), TBA (29), cisplatin (30,31), and quinine (32) interacted with metformin either through competition or through inhibition of OCTs or MATEs, and other drug classes such as tyrosine kinase inhibitors (33) or b-blockers (34) are potential substrates for OCT2 or MATEs, further stressing the importance of developing noninvasive methods to study these interactions. The present study confirms that there is drug-drug interaction, but whether this occurs via OCT or MATE or both needs to be addressed fully.…”