The evolution of the OATP hepatic uptake transport protein family in DMPK sciences: from obscure liver transporters to key determinants of hepatobiliary clearance

Fenner, Katherine; Jones, Hannah M.; Ullah, Mohammed; Kempshall, Sarah; Dickins, Maurice; Lai, Yurong; Morgan, Paul; Barton, Hugh A.

doi:10.3109/00498254.2011.626464

Cited by 52 publications

(32 citation statements)

References 135 publications

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“…The biliary elimination of apixaban was not markedly affected by the transporter knockout or the transporter inhibitor mainly due to the fact that liver uptake is the driving force for the biliary elimination (Watanabe et al, 2009;Fenner et al, 2012;Varma et al, 2012) and apixaban was not a substrate for hepatic uptake transporters OATP1B1/3 or OAT1/3 (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats

Zhang

Frost

et al. 2013

Drug Metab Dispos

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The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile ductcannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.

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Section: Discussionmentioning

confidence: 99%

Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats

Zhang

Frost

et al. 2013

Drug Metab Dispos

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“…OATP1B1 and OATP1B3 exhibit broad and overlapping substrate specificities for endogenous and exogenous compounds including thyroid hormones, bile acids, repaglinide, and several statins (Hagenbuch and Gui, 2008). The importance of these hepatic transporters has been illustrated by recent studies showing that OATP1B-mediated transport can be the rate-determining step of hepatobiliary drug clearance (Fenner et al, 2012). Moreover, OATP1B inhibition or induction may be the underlying mechanism of clinically relevant drug-drug interactions (Müller and Fromm, 2011;Shitara, 2011).…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Identification of OATP1B1/3 Inhibitors

et al. 2013

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Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1-or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 mM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentrationdependent inhibition was also determined, yielding K i values ranging from 0.06 to 6.5 mM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.

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“…Organic anion-transporting polypeptides (hOATP1B1, hOATP1B3, hOATP2B1) and organic cation transporter 1 (OCT1) on the sinusoidal membrane are involved in the hepatic uptake of several drugs (Shitara et al, 2006;Fahrmayr et al, 2010;Fenner et al, 2012). Among these, OATP1B1 and OATP1B3 are selectively expressed in the human liver and exhibit reasonably broad substrate specificities, suggesting the importance of these transporters in the hepatic uptake of many clinically important anionic drugs.…”

Section: Introductionmentioning

confidence: 99%

Physicochemical Property Space of Hepatobiliary Transport and Computational Models for Predicting Rat Biliary Excretion

Varma

Chang²,

Lai³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Biliary excretion (BE) is a major elimination pathway, and its prediction is particularly important for optimization of systemic and/or target-site exposure of new molecular entities. The objective is to characterize the physicochemical space associated with hepatobiliary transport and rat BE and to develop in silico models. BE of 123 in-house compounds was obtained using the bile-duct cannulated rat model. Human and rat hepatic uptake transporters (hOATP1B1, hOATP1B3, hOATP2B1, and rOatp1b2) substrates (n ‫؍‬ 183) were identified using transfected cells. Furthermore, the datasets were extended by adding BE of 163 compounds and 97 organic anion transporting polypeptide (OATP) substrates from the literature. Approximately 60% of compounds showing percentage of BE (%BE) > 10 are anions, with mean BE of anions (36%) more than 3-fold higher than that of nonacids (11%). Compounds with %BE > 10 are found to have high molecular mass, large polar surface area, more rotatable bonds, and high H-bond count, whereas the lipophilicity and passive membrane permeability are lower compared with compounds with %BE < 10. According to statistical analysis and principal component analysis, hOATPs and rOatp1b2 substrates showed physicochemical characteristics that were similar to those of the %BE > 10 dataset. We further build categorical in silico models to predict rat BE, and the models (gradient boosting machine and scoring function) developed showed 80% predictability in identifying the rat BE bins (%BE > 10 or < 10). In conclusion, the significant overlap of the property space of OATP substrates and rat BE suggests a predominant role of sinusoidal uptake transporters in biliary elimination. Categorical in silico models to predict rat BE were developed, and successful predictions were achieved.

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The evolution of the OATP hepatic uptake transport protein family in DMPK sciences: from obscure liver transporters to key determinants of hepatobiliary clearance

Cited by 52 publications

References 135 publications

Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats

Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats

Structure-Based Identification of OATP1B1/3 Inhibitors

Physicochemical Property Space of Hepatobiliary Transport and Computational Models for Predicting Rat Biliary Excretion

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