Application of QSAR analysis to organic anion transporting polypeptide 1a5 (Oatp1a5) substrates

Yarım, Mine; Moro, Stefano; Huber, R.; Meier, Peter J.; Kaseda, Chosei; Kashima, Toru; Hagenbuch, Bruno; Folkers, Gerd

doi:10.1016/j.bmc.2004.10.009

Cited by 24 publications

(12 citation statements)

References 10 publications

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“…A notable exception is a recent study by Yarim and coworkers on rat oatp1a5 (Yarim et al, 2005) who used comparative molecular field analysis on 18 substrates. An improved understanding of the structural requirements of the OATPs may explain the mechanisms underlying the reported drug-drug interactions as due to transporter inhibition (Kim, 2003).…”

Section: Discussionmentioning

confidence: 99%

Comparative Pharmacophore Modeling of Organic Anion Transporting Polypeptides: A Meta-Analysis of Rat Oatp1a1 and Human OATP1B1

Chang¹,

Pang²,

Swaan³

et al. 2005

J Pharmacol Exp Ther

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The organic anion transporting polypeptides OATPs are key membrane transporters for which crystal structures are not currently available. They transport a diverse array of xenobiotics and are expressed at the interface of hepatocytes, renal tubular cells, enterocytes, and the choroid plexus. To aid the understanding of the key molecular features for substratetransporter interactions, pharmacophore models were produced for the two OATPs that have been most extensively studied, namely rat Oatp1a1 and human OATP1B1. Literature data from Chinese hamster ovary, HeLa, human embryonic kidney 293 cells, and Xenopus laevis oocytes were used to construct pharmacophores for each individual transporter which were later merged to show similarities across cell lines for the same transporter. Additionally, meta-pharmacophores were generated from the combined datasets of each cell system used with the same transporter. The pharmacophores for each transporter consisted of hydrogen bond acceptor and hydrophobic features. There was good agreement between the merged and meta-pharmacophores containing two hydrogen bond acceptors and two or three hydrophobic features for Oatp1a1 and OATP1B1. External test sets were used to validate the individual pharmacophores. The meta-pharmacophores were also used to make predictions for molecules not included in the models and provided new molecular insight into the key features for these OATP transporters. This approach can be extended to other transporters for which limited data are available.

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Section: Discussionmentioning

confidence: 99%

Comparative Pharmacophore Modeling of Organic Anion Transporting Polypeptides: A Meta-Analysis of Rat Oatp1a1 and Human OATP1B1

Chang¹,

Pang²,

Swaan³

et al. 2005

J Pharmacol Exp Ther

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“…However, evaluation of other cell expression systems indicated that transfected COS cells exhibited an acceptable background for radiolabeled macrolide uptake. In transfected COS cells, rat Oatp1a5 exhibited significant uptake of 5 M [ 3 H]estrone-3-sulfate, a prototypical low-affinity Oatp1a5 substrate (Yarim et al, 2005), that was approximately 9-fold over background. However, there was no ), or erythromycin (41.4 Ϯ 11.7 pmol ⅐ mg cell protein Ϫ1 ⅐ 10 min Ϫ1 ) was set at 100%.…”

Section: Inhibition Of Taurocholate Uptake By Macrolides In Ratmentioning

confidence: 99%

Interaction of Macrolide Antibiotics with Intestinally Expressed Human and Rat Organic Anion-Transporting Polypeptides

Lan¹,

Rao²,

Haywood³

et al. 2009

Drug Metab Dispos

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ABSTRACT:The macrolide antibiotics azithromycin and clarithromycin are large molecular weight compounds that exhibit moderate to excellent oral bioavailability in preclinical species and humans. Previous concomitant dosing studies in rats using rifamycin SV, a general organic anion-transporting polypeptide (OATP) inhibitor, suggested that the high oral absorption of azithromycin and clarithromycin may be caused by facilitative uptake by intestinal Oatps. In this study, we used OATP/Oatp-expressing cells to investigate the interaction of macrolides with rat Oatp1a5, human OATP1A2, and human/rat OATP2B1/Oatp2b1. These experiments showed that azithromycin and clarithromycin were potent inhibitors of rat Oatp1a5-mediated taurocholate uptake with apparent inhibitor constant (K i ) values of 3.3 and 2.4 M, respectively. The macrolides functioned as noncompetitive inhibitors but were not transport substrates for rat Oatp1a5, as assessed by direct uptake measurements of radiolabeled azithromycin and clarithromycin. cis-Inhibition and direct uptake studies further showed that azithromycin and clarithromycin were only very weak inhibitors and not substrates for human OATP1A2 and human/rat OATP2B1/Oatp2b1. In summary, these results indicate that the macrolides azithromycin and clarithromycin potently inhibit rat Oatp1a5 but do not significantly interact with OATP1A2 and OATP2B1/Oatp2b1. These intestinally expressed OATP/Oatp(s) are not responsible for the postulated facilitative uptake of azithromycin and clarithromycin, and alternative facilitative pathways must exist for their intestinal absorption.

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“…An example of this type of multispecificity are members of the organic anion transporting polypeptide carriers Oatps (SLC21 / SLCO) which transport weak organic acids, neutral compounds and even a few cationic compounds (Hagenbuch and Meier 2003). Quantitative structure-activity relationships (QSARs) (Yarim et al 2005) were elaborated to predict structural criteria of compounds essentially needed to fulfill the requirements for transport by individual carrier proteins. Systems in the liver and kidney have been reviewed in detail (Van Montfoort et al 2003;Hagenbuch and Meier 2003;Chandra and Brouwer 2004).…”

Section: An Extended Phase Conceptmentioning

confidence: 99%

Drug transporters in pharmacokinetics

Petzinger¹,

Geyer²

2006

Naunyn Schmied Arch Pharmacol

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This review deals with the drug transporters allowing drugs to enter and leave cells by carrier-mediated pathways. Emphasis is put on liver transporters but systems in gut, kidney, and blood-brain barrier are mentioned as well. Drug-drug interactions on carriers may provoke significant modification in pharmacokinetics as do carrier gene polymorphisms yielding functional carrier protein mutations. An integrated phase concept should reflect the interplay between drug metabolism and drug transport.

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Application of QSAR analysis to organic anion transporting polypeptide 1a5 (Oatp1a5) substrates

Cited by 24 publications

References 10 publications

Comparative Pharmacophore Modeling of Organic Anion Transporting Polypeptides: A Meta-Analysis of Rat Oatp1a1 and Human OATP1B1

Comparative Pharmacophore Modeling of Organic Anion Transporting Polypeptides: A Meta-Analysis of Rat Oatp1a1 and Human OATP1B1

Interaction of Macrolide Antibiotics with Intestinally Expressed Human and Rat Organic Anion-Transporting Polypeptides

Drug transporters in pharmacokinetics

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