Organic Cation Transporter 1 an Intestinal Uptake Transporter: Fact or Fiction?

Abstract

Intestinal transporter proteins are known to affect the pharmacokinetics and in turn the efficacy and safety of many orally administered drugs in a clinically relevant manner. This knowledge is especially well-established for intestinal ATP-binding cassette transporters such as P-gp and BCRP. In contrast to this, information about intestinal uptake carriers is much more limited although many hydrophilic or ionic drugs are not expected to undergo passive diffusion but probably require specific uptake transporters. A transporter which is controversially discussed with respect to its expression, localization and function in the human intestine is the organic cation transporter 1 (OCT1). This review article provides an up-to-date summary on the available data from expression analysis as well as functional studies in vitro, animal findings and clinical observations. The current evidence suggests that OCT1 is expressed in the human intestine in small amounts (on gene and protein levels), while its cellular localization in the apical or basolateral membrane of the enterocytes remains to be finally defined, but functional data point to a secretory function of the transporter at the basolateral membrane. Thus, OCT1 should not be considered as a classical uptake transporter in the intestine but rather as an intestinal elimination pathway for cationic compounds from the systemic circulation.

Drug Disposition Protein Quantification in Matched Human Jejunum and Liver From Donors With Obesity

“… 46 These are likely contributors to why we could not quantify some low abundant drug transporters, including a few of those identified by the International Transporter Consortium (ITC) 34 as relevant for human pharmacokinetics, or other potentially important drug transporters. 47 For example, we could not detect the liver drug transporters ABCC4 and ABCG2, and only identified ABCC6 in few donors, and then with only one peptide. Importantly, ABCG2 has also previously only been found at very low levels with global proteomics in whole tissue lysates, 15 while others could not quantify the protein with global proteomics even after membrane enrichment.…”

“…In addition, peptides from low abundant transporters can be “masked” if co‐eluting with those from high abundant proteins in global proteomics MS analysis 46 . These are likely contributors to why we could not quantify some low abundant drug transporters, including a few of those identified by the International Transporter Consortium (ITC) 34 as relevant for human pharmacokinetics, or other potentially important drug transporters 47 . For example, we could not detect the liver drug transporters ABCC4 and ABCG2, and only identified ABCC6 in few donors, and then with only one peptide.…”

Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine, liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin

“…Clinical report also shows that OCT1 genotypes do not affect steady-state pharmacokinetics of metformin in human. These results indicate that intestinal OCT1 seems not to be principally involved in metformin absorption 60 . Protein expressions of Oct2, Oct3 and Thtr2 are detected in small intestine of rats.…”

Evaluation of the Impact of Ritlecitinib on Organic Cation Transporters Using Sumatriptan and Biomarkers as Probes

“…[30][31][32][33][34][35] It should be noted that NMN also presents as an OCT1 substrate in vitro, although it is largely cleared renally (≈80%), similar to metformin via OCT2, MATE1, and MATE2K, and so was included in vitro in order to support the study of OCT1 inhibition substrate dependency. 24,36 The major inactive circulating metabolite of ritlecitinib, M2, was also evaluated in the in vitro uptake studies and found to be an OCT1 inhibitor, with a substrate dependency for sumatriptan versus metformin and IBC. In a human radio-labeled study, ritlecitinib was the most prevalent circulating species (30.4% of circulating radioactivity) after oral administration, and M2 was the major metabolite (16.5%) of ritlecitinib and pharmacologically inactive (Pfizer, data on file).…”

“…In addition, the contribution of OCT1 (or other transporters) expressed in the intestine is not considered. 23,24 It should be noted that plasma C max of orally dosed sumatriptan is not impacted in carriers of SLC22A1 loss-of-function alleles. 7 This implies that intestinal OCT1 does not play a major role in the PK of sumatriptan.…”