Drug specificity and intestinal membrane localization of human organic cation transporters (OCT)

Müller, Johanna; Lips, Katrin Susanne; Metzner, Linda; Neubert, Reinhard H.H.; Koepsell, Hermann; Brandsch, Matthias

doi:10.1016/j.bcp.2005.09.011

Cited by 225 publications

(168 citation statements)

References 37 publications

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“…These data suggested that OCT3 plays an important role in metformin absorption in vivo. OCT1 is localized to the basolateral membrane of the enterocyte, and is suspected to play a major role in metformin absorption by mediating its flux across the basolateral membrane of enterocytes to the portal circulation 37,38 .…”

Section: Transporters Involved In Metformin Intestinal Absorptionmentioning

confidence: 99%

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

Liang

Giacomini

2017

Journal of Pharmaceutical Sciences

127

113

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Metformin, widely used as first-line treatment for type 2 diabetes, exists primarily as a hydrophilic cation at physiological pHs. As such, membrane transporters play a substantial role in its absorption, tissues distribution, and renal elimination. Multiple organic cation transporters are determinants of the pharmacokinetics of metformin, and many of them are important in its pharmacological action, as mediators of metformin entry into target tissues. Further, a recent genomewide association study (GWAS) in a large multi-ethnic population implicated polymorphisms in SLC2A2, encoding the glucose transporter, GLUT2, as important determinants of response to metformin. Here, we describe the key transporters associated with metformin pharmacokinetics and response.

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Section: Transporters Involved In Metformin Intestinal Absorptionmentioning

confidence: 99%

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

Liang

Giacomini

2017

Journal of Pharmaceutical Sciences

127

113

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“…There are three members of the human OCT family: hOCT1 is expressed primarily in the liver; hOCT2 in the kidney; and hOCT3 in the liver, heart, brain, and placenta (12). All are present in the intestinal/colorectal area to varying degrees (11,13). OCTs interact with organic substrates having M r Ͻ400 Da and overall positive charge (12).…”

mentioning

confidence: 99%

cis -Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects

Lovejoy

Todd

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

226

221

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We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex, cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH 3)2(py)Cl]؉ or cDPCP, a coordination compound previously identified to have significant anticancer activity in a mouse tumor model. This compound is an excellent substrate for organic cation transporters 1 and 2, also designated SLC22A1 and SLC22A2, respectively. These transporters are abundantly expressed in human colorectal cancers, where they mediate uptake of oxaliplatin, cis-[Pt(DACH)(oxalate)] (DACH ‫؍‬ trans-R,R-1,2-diaminocyclohexane), an FDA-approved first-line therapy for colorectal cancer. Unlike oxaliplatin, however, cDPCP binds DNA monofunctionally, as revealed by an x-ray crystal structure of cis-{Pt(NH 3)2(py)} 2؉ bound to the N7 atom of a single guanosine residue in a DNA dodecamer duplex. Although the quaternary structure resembles that of B-form DNA, there is a base-pair step to the 5 side of the Pt adduct with abnormally large shift and slide values, features characteristic of cisplatin intrastrand cross-links. cDPCP effectively blocks transcription from DNA templates carrying adducts of the complex, unlike DNA lesions of other monofunctional platinum(II) compounds like {Pt(dien)} 2؉ . cDPCP-DNA adducts are removed by the nucleotide excision repair apparatus, albeit much less efficiently than bifunctional platinum-DNA intrastrand cross-links. These exceptional characteristics indicate that cDPCP and related complexes merit consideration as therapeutic options for treating colorectal and other cancers bearing appropriate cation transporters.cancer therapy ͉ nucleotide excision repair ͉ organic cation transporter ͉ RNA polymerase II inhibition ͉ x-ray crystal structure

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“…Few of the ophthalmic drugs that are transported by OCT are atropine, timolol, ofloxacin, and levofloxacin. [9][10][11][12] In eye, these transporters are expressed in various ocular tissues like the cornea, iris, ciliary body, conjunctiva, and retina. 13 Targeting these transporters will be a smart way of drug delivery aimed at optimal ocular bioavailability.…”

Section: Introductionmentioning

confidence: 99%

“…It is well known that tetraethylammonium chloride (TEA) and metformin are cation substrates of OCT, and atropine and quinidine can inhibit the uptake of cation substrates. 9,[21][22][23][24] Hence, in the present study we used these substrates and inhibitors to understand the role of OCT in modulating the transport of their substrates across the cornea after topical application.…”

Section: Introductionmentioning

confidence: 99%