scholarly journals Preclinical Evaluation of [18F]LCATD as a PET Tracer to Study Drug-Drug Interactions Caused by Inhibition of Hepatic Transporters

2018 ◽  
Vol 2018 ◽  
pp. 1-10
Author(s):  
Andrea Testa ◽  
Sergio Dall’Angelo ◽  
Marco Mingarelli ◽  
Andrea Augello ◽  
Lutz Schweiger ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Lithocholic Acid ◽  
Hepatic Uptake ◽  
Drug Induced ◽  
Liver Uptake ◽  
Rifamycin Sv ◽  
Pet Tracer ◽  
Hepatic Transporters ◽  
Uptake Transporters

The bile acid analogue [18F]LCATD (LithoCholic Acid Triazole Derivative) is transported in vitro by hepatic uptake transporters such as OATP1B1 and NTCP and efflux transporter BSEP. In this in vivo “proof of principle” study, we tested if [18F]LCATD may be used to evaluate drug-drug interactions (DDIs) caused by inhibition of liver transporters. Hepatic clearance of [18F]LCATD in rats was significantly modified upon coadministration of rifamycin SV or sodium fusidate, which are known to inhibit clinically relevant uptake transporters (OATP1B1, NTCP) and canalicular hepatic transporters (BSEP) in humans. Treatment with rifamycin SV (total dose 62.5 mg·Kg−1) reduced the maximum radioactivity of [18F]LCATD recorded in the liver from 14.2 ± 0.8% to 10.2 ± 0.9% and delayed t_max by 90 seconds relative to control rats. AUCliver 0–5 min, AUCbile 0–10 min and hepatic uptake clearance CLuptake,in vivo of rifamycin SV treated rats were significantly reduced, whereas AUCliver 0–30 min was higher than in control rats. Administration of sodium fusidate (30 mg·Kg−1) inhibited the liver uptake of [18F]LCATD, although to a lesser extent, reducing the maximum radioactivity in the liver to 11.5 ± 0.3%. These preliminary results indicate that [18F]LCATD may be a good candidate for future applications as an investigational tracer to evaluate altered hepatobiliary excretion as a result of drug-induced inhibition of hepatic transporters.

scholarly journals Carrier-Mediated Delivery of 9-(2-Phosphonylmethoxyethyl)Adenine to Parenchymal Liver Cells: a Novel Therapeutic Approach for Hepatitis B

2000 ◽  
Vol 44 (3) ◽  
pp. 477-483 ◽  
Author(s):  
Remco L. A. de Vrueh ◽  
Erik T. Rump ◽  
Erika van de Bilt ◽  
Richard van Veghel ◽  
Jan Balzarini ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Lithocholic Acid ◽  
Hepatic Uptake ◽  
Liver Cells ◽  
Asialoglycoprotein Receptor ◽  
Parenchymal Liver ◽  
Lipophilic Prodrug ◽  
Acid Labile

ABSTRACT Our aim is to selectively deliver 9-(2-phosphonylmethoxyethyl)adenine (PMEA) to parenchymal liver cells, the primary site of hepatitis B virus (HBV) infection. Selective delivery is necessary because PMEA, which is effective against HBV in vitro, is hardly taken up by the liver in vivo. Lactosylated reconstituted high-density lipoprotein (LacNeoHDL), a lipid particle that is specifically internalized by parenchymal liver cells via the asialoglycoprotein receptor, was used as the carrier. PMEA could be incorporated into the lipid moiety of LacNeoHDL by attaching, via an acid-labile bond, lithocholic acid-3α-oleate to the drug. The uptake of the lipophilic prodrug (PMEA-LO) by the liver was substantially increased after incorporation into LacNeoHDL. Thirty minutes after injection of [3H]PMEA-LO-loaded LacNeoHDL into rats, the liver contained 68.9% ± 7.7% of the dose (free [3H]PMEA, <5%). Concomitantly, the uptake by the kidney was reduced to <2% of the dose (free [3H]PMEA, >45%). The hepatic uptake of PMEA-LO-loaded LacNeoHDL occurred mainly by parenchymal cells (88.5% ± 8.2% of the hepatic uptake). Moreover, asialofetuin inhibited the liver association by >75%, indicating uptake via the asialoglycoprotein receptor. The acid-labile linkage in PMEA-LO, designed to release PMEA during lysosomal processing of the prodrug-loaded carrier, was stable at physiological pH but was hydrolyzed at lysosomal pH (half-life, 60 to 70 min). Finally, subcellular fractionation indicates that the released PMEA is translocated to the cytosol, where it is converted into its active diphosphorylated metabolite. In conclusion, lipophilic modification and incorporation of PMEA into LacNeoHDL improves the biological fate of the drug and may lead to an enhanced therapeutic efficacy against chronic hepatitis B.

scholarly journals Raltegravir Has a Low Propensity To Cause Clinical Drug Interactions through Inhibition of Major Drug Transporters: anIn VitroEvaluation

2013 ◽  
Vol 58 (3) ◽  
pp. 1294-1301 ◽  
Author(s):  
Matthew L. Rizk ◽  
Robert Houle ◽  
Grace Hoyee Chan ◽  
Mike Hafey ◽  
Elizabeth G. Rhee ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Cation ◽  
Drug Transporters ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Hepatic Uptake ◽  
Efflux Transporters ◽  
Renal Uptake ◽  
No Inhibition ◽  
Uptake Transporters

ABSTRACTRaltegravir (RAL) is a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. The potential of RAL to cause transporter-related drug-drug interactions (DDIs) as an inhibitor has not been well described to date. In this study, a series ofin vitroexperiments were conducted to assess the inhibitory effects of RAL on major human drug transporters known to be involved in clinically relevant drug interactions, including hepatic and renal uptake transporters and efflux transporters. For hepatic uptake transporters, RAL showed no inhibition of organic anion-transporting polypeptide 1B1 (OATP1B1), weak inhibition of OATP1B3 (40% inhibition at 100 μM), and no inhibition of organic cation transporter 1 (OCT1). Studies of renal uptake transporters showed that RAL inhibited organic anion transporters 1 and 3 (OAT1 and OAT3) with 50% inhibitory concentrations (IC50s) (108 μM and 18.8 μM, respectively) well above the maximum concentration of drug in plasma (Cmax) at the clinical 400-mg dose and did not inhibit organic cation transporter 2 (OCT2). As for efflux transporters, RAL did not inhibit breast cancer resistance protein (BCRP) and showed weak inhibition of multidrug and toxin extrusion protein 1 (MATE1) (52% inhibition at 100 μM) and MATE2-K (29% inhibition at 100 μM). These studies indicate that at clinically relevant exposures, RAL does not inhibit or only weakly inhibits hepatic uptake transporters OATP1B1, OATP1B3, and OCT1, renal uptake transporters OCT2, OAT1, and OAT3, as well as efflux transporters BCRP, MATE1, and MATE2-K. The propensity for RAL to cause DDIs via inhibition of these transporters is therefore considered low.

In Vitro Characterization of Axitinib Interactions with Human Efflux and Hepatic Uptake Transporters: Implications for Disposition and Drug Interactions

2013 ◽  
Vol 41 (8) ◽  
pp. 1575-1583 ◽  
Author(s):  
Eric L. Reyner ◽  
Samantha Sevidal ◽  
Mark A. West ◽  
Andrea Clouser-Roche ◽  
Sascha Freiwald ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Hepatic Uptake ◽  
In Vitro Characterization ◽  
Uptake Transporters

Kinetics and uptake in vivo of oxidatively modified lymph chylomicrons

1995 ◽  
Vol 268 (4) ◽  
pp. G709-G716
Author(s):  
Y. Umeda ◽  
T. G. Redgrave ◽  
B. C. Mortimer ◽  
J. C. Mamo
Keyword(s):  
Fish Oil ◽  
Corn Oil ◽  
Reticuloendothelial System ◽  
Hepatic Uptake ◽  
Slow Phase ◽  
Liver Uptake ◽  
Rapid Phase ◽  
Oxidatively Modified ◽  
Oil Particles

The metabolism of oxidized chylomicrons (ox-CMs) was investigated in vivo. CMs from rats fed corn, linseed, or fish oil were oxidized by incubation with 2,2'-azobis(2-amidinopropane)hydrochloride (AAPH) or sodium hypochlorite (NaOCl). Oxidized CMs had a rapid phase of clearance, followed by a slow phase. Clearance of ox-CMs was decreased for corn oil but increased for linseed and fish oil particles. Differences in rats of uptake between CM types or treatment were independent of the rate of remnant formation, but were instead a consequence of decreased clearance. A greater triglyceride-to-cholesteryl ester ratio in liver suggested that there was less lipolysis of ox-CM triglyceride prior to uptake. Hepatic uptake of ox-CMs was decreased, whereas there was increased uptake in spleen. However, the uptake by Kupffer cells of ox-CMs was 43% of total liver uptake after AAPH treatment and 59% after NaOCl treatment, compared with 21% for control CMs. Collectively, our data show that oxidation can have differential effects on the rate of clearance of CMs and that ox-CMs are preferentially cleared by the reticuloendothelial system.

Model-based approaches to predict drug–drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond

2013 ◽  
Vol 9 (4) ◽  
pp. 459-472 ◽  
Author(s):  
Hugh A Barton ◽  
Yurong Lai ◽  
Theunis C Goosen ◽  
Hannah M Jones ◽  
Ayman F El-Kattan ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Hepatic Uptake ◽  
Model Based ◽  
Uptake Transporters

scholarly journals Role of OATP1B1 and OATP1B3 in Drug-Drug Interactions Mediated by Tyrosine Kinase Inhibitors

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 856
Author(s):  
Dominique A. Garrison ◽  
Zahra Talebi ◽  
Eric D. Eisenmann ◽  
Alex Sparreboom ◽  
Sharyn D. Baker
Keyword(s):  
Tyrosine Kinase ◽  
Drug Interactions ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Hepatic Uptake ◽  
Medical Intervention ◽  
Chemotherapeutic Agents ◽  
Comprehensive Overview ◽  
Regulatory Documents ◽  
Uptake Transporters

Failure to recognize important features of a drug’s pharmacokinetic characteristics is a key cause of inappropriate dose and schedule selection, and can lead to reduced efficacy and increased rate of adverse drug reactions requiring medical intervention. As oral chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) are particularly prone to cause drug-drug interactions as many drugs in this class are known or suspected to potently inhibit the hepatic uptake transporters OATP1B1 and OATP1B3. In this article, we provide a comprehensive overview of the published literature and publicly-available regulatory documents in this rapidly emerging field. Our findings indicate that, while many TKIs can potentially inhibit the function of OATP1B1 and/or OATP1B3 and cause clinically-relevant drug-drug interactions, there are many inconsistencies between regulatory documents and the published literature. Potential explanations for these discrepant observations are provided in order to assist prescribing clinicians in designing safe and effective polypharmacy regimens, and to provide researchers with insights into refining experimental strategies to further predict and define the translational significance of TKI-mediated drug-drug interactions.

scholarly journals Automated Applications of Sandwich-Cultured Hepatocytes in the Evaluation of Hepatic Drug Transport

2011 ◽  
Vol 16 (4) ◽  
pp. 427-435 ◽  
Author(s):  
Cassandra H. Perry ◽  
William R. Smith ◽  
Robert L. St. Claire ◽  
Kenneth R. Brouwer
Keyword(s):  
Drug Discovery ◽  
Drug Transport ◽  
Hepatic Uptake ◽  
Potential Operator ◽  
Cultured Hepatocytes ◽  
Drug Induced ◽  
Hepatic Drug ◽  
Hepatobiliary Disposition

Predictions of the absorption, distribution, metabolism, excretion, and toxicity of compounds in pharmaceutical development are essential aspects of the drug discovery process. B-CLEAR is an in vitro system that uses sandwich-cultured hepatocytes to evaluate and predict in vivo hepatobiliary disposition (hepatic uptake, biliary excretion, and biliary clearance), transporter-based hepatic drug-drug interactions, and potential drug-induced hepatotoxicity. Automation of predictive technologies is an advantageous and preferred format in drug discovery. In this study, manual and automated studies are investigated and equivalence is demonstrated. In addition, automated applications using model probe substrates and inhibitors to assess the cholestatic potential of drugs and evaluate hepatic drug transport are examined. The successful automation of this technology provides a more reproducible and less labor-intensive approach, reducing potential operator error in complex studies and facilitating technology transfer.

Hepatobiliary Kinetics of 113mIn-Phenolphthalexon

1981 ◽  
Vol 20 (02) ◽  
pp. 90-93
Author(s):  
P.B. Parab ◽  
U.R. Raikar ◽  
R.D. Ganatra ◽  
M. C. Patel
Keyword(s):  
Biliary Excretion ◽  
Iminodiacetic Acid ◽  
Organ Distribution ◽  
Liver Uptake ◽  
On Line ◽  
Rapid Clearance ◽  
Chemical Purity ◽  
Kinetics Of ◽  
High Liver

Phenolphthalexon, a compound with iminodiacetic acid as a functional group, has been labelled with 113mIn to high chemical purity and its usefulness in studies of biliary excretion patency has been studied. Organ distribution of 113mIn-phenolphthalexon in mice was characterized by high liver uptake (50.8% of the administered dose after 5 min) and rapid clearance through the gall bladder. An animal model for studying obstruction of biliary excretion has been developed. Data on the kinetics of the radiopharmaceutical were obtained by collecting in-vivo data through an on-line computer.

Uptake, Internalization and Degradation of the Novel Plasminogen Activator Reteplase (BM 06.022) in the Rat

1995 ◽  
Vol 74 (06) ◽  
pp. 1501-1510 ◽  
Author(s):  
J Kuiper ◽  
H van de Bilt ◽  
U Martin ◽  
Th J C van Berkel
Keyword(s):  
Plasminogen Activator ◽  
Liver Cells ◽  
The Novel ◽  
Uptake Mechanism ◽  
Liver Uptake ◽  
Lysosomal Compartment ◽  
Β Phase ◽  
Α Phase ◽  
Parenchymal Liver

SummaryThe catabolism of the novel plasminogen activator reteplase (BM 06.022) was described. For this purpose BM 06.022 was radiolabelled with l25I or with the accumulating label l25I-tyramine cellobiose (l25I-TC).BM 06.022 was injected at a pharmacological dose of 380 μg/kg b.w. and it was cleared from the plasma in a biphasic manner with a half-life of about 1 min in the α-phase and t1/2of 20-28 min in the β-phase. 28% and 72% of the injected dose was cleared in the α-phase and β-phase, respectively. Initially liver, kidneys, skin, bones, lungs, spleen, and muscles contributed mainly to the plasma clearance. Only liver and the kidneys, however, were responsible for the uptake and subsequent degradation of BM 06.022 and contributed for 75% to the catabolism of BM 06.022. BM 06.022 was degraded in the lysosomal compartment of both organs. Parenchymal liver cells were responsible for 70% of the liver uptake of BM 06.022. BM 06.022 associated rapidly to isolated rat parenchymal liver cells and was subsequently degraded in the lysosomal compartment of these cells. BM 06.022 bound with low-affinity to the parenchymal liver cells (550 nM) and the binding of BM 06.022 could be displaced by t-PA (IC50 5.6 nM), indicating that the low-density lipoprotein receptor-related protein (LRP) could be involved in the binding of BM 06.022. GST-RAP, which is an inhibitor of LRP, could in vivo significantly inhibit the uptake of BM 06.022 in the liver.It is concluded that BM 06.022 is metabolized primarily in the liver and the kidneys. These organs take up and degrade BM 06.022 in the lysosomes. The uptake mechanism of BM 06.022 in the kidneys is unknown, while LRP is responsible for a low-affinity binding and uptake of BM 06.022 in parenchymal liver cells.

Sign in / Sign up

Export Citation Format

Share Document