Evaluation of the Usefulness of Breast Cancer Resistance Protein (BCRP) Knockout Mice and BCRP Inhibitor-Treated Monkeys to Estimate the Clinical Impact of BCRP Modulation on the Pharmacokinetics of BCRP Substrates

Published on May 1, 2015in Pharmaceutical Research3.242
· DOI :10.1007/S11095-014-1563-4
Tsuyoshi Karibe4
Estimated H-index: 4
(Daiichi Sankyo),
Rie Hagihara-Nakagomi1
Estimated H-index: 1
(Daiichi Sankyo)
+ 7 AuthorsTakashi Izumi17
Estimated H-index: 17
(Daiichi Sankyo)
Sources
Abstract
Purpose To evaluate whether the impact of functional modulation of the breast cancer resistance protein (BCRP, ABCG2 421C>A) on human pharmacokinetics after oral administration is predictable using Bcrp knockout mice and cynomolgus monkeys pretreated with a BCRP inhibitor, elacridar.
📖 Papers frequently viewed together
97 Citations
2,305 Citations
28 Citations
References39
Newest
#1Sindhuja Selvakumar (BMS: Bristol-Myers Squibb)H-Index: 1
#2Priyadeep Bhutani (BMS: Bristol-Myers Squibb)H-Index: 4
Last. Murali SubramanianH-Index: 8
view all 11 authors...
Cynomolgus monkeys are a commonly used species in preclinical drug discovery, and have high genetic similarity to humans, especially for the drug-metabolizing cytochrome P450s. However, species differences are frequently observed in the metabolism of drugs between cynomolgus monkeys and humans, and delineating these differences requires expressed CYPs. Toward this end, cynomolgus monkey CYP3A4 (c3A4) was cloned and expressed in a novel human embryonic kidney 293-6E cell suspension system. Follow...
6 CitationsSource
#1Tsuyoshi Takahashi (Mitsubishi Tanabe Pharma)H-Index: 5
#2Tatsuyuki Ohtsuka (Mitsubishi Tanabe Pharma)H-Index: 4
Last. Toshiyuki Kume (Mitsubishi Tanabe Pharma)H-Index: 15
view all 8 authors...
Drug–drug interactions (DDIs) caused by the inhibition of hepatic uptake transporters such as organic anion transporting polypeptide (OATP) can affect therapeutic efficacy and cause adverse reactions. We investigated the potential utility of pitavastatin as an in vivo probe substrate for preclinically studying OATP-mediated DDIs using cynomolgus monkeys. Cyclosporine A (CsA) and rifampicin (RIF), typical OATP inhibitors, inhibited active uptake of pitavastatin into monkey hepatocytes with half-m...
28 CitationsSource
#1Tomoki Imaoka (Daiichi Sankyo)H-Index: 6
#2Tsuyoshi Mikkaichi (Daiichi Sankyo)H-Index: 8
Last. Takashi Izumi (Daiichi Sankyo)H-Index: 17
view all 6 authors...
Cumulative studies describe the importance of drug transporters as one of the key determinants of pharmacokinetics that necessitate investigation and assessment of the involvement of drug transporters in drug discovery and development. The present study investigated an integrated in vivo and in vitro approach to determine the involvement of organic anion transporting polypeptides (Oatps) in the disposition of drugs in rats using rifampicin as an inhibitor. When bromosulfophthalein (BSP) and HMG-...
14 CitationsSource
#1Hong Shen (BMS: Bristol-Myers Squibb)H-Index: 17
#2Zheng Yang (BMS: Bristol-Myers Squibb)H-Index: 30
Last. A. David Rodrigues (BMS: Bristol-Myers Squibb)H-Index: 30
view all 15 authors...
Organic anion–transporting polypeptides (OATP) 1B1, 1B3, and 2B1 can serve as the loci of drug–drug interactions (DDIs). In the present work, the cynomolgus monkey was evaluated as a potential model for studying OATP-mediated DDIs. Three cynomolgus monkey OATPs (cOATPs), with a high degree of amino acid sequence identity (91.9, 93.5, and 96.6% for OATP1B1, 1B3, and 2B1, respectively) to their human counterparts, were cloned, expressed, and characterized. The cOATPs were stably transfected in hum...
59 CitationsSource
#1Liyue Huang (Amgen)H-Index: 17
#2Xuhai Be (Amgen)H-Index: 9
Last. Lixia Jin (Amgen)H-Index: 1
view all 9 authors...
This study was designed to characterize breast cancer resistance protein (Bcrp) knockout Abcg2 (−/−) rats and assess the effect of ATP-binding cassette subfamily G member 2 ( Abcg2 ) deletion on the excretion and pharmacokinetic properties of probe substrates. Deletion of the target gene in the Abcg2 (−/−) rats was confirmed, whereas gene expression was unaffected for most of the other transporters and metabolizing enzymes. Biliary excretion of nitrofurantoin, sulfasalazine, and compound A [2-(5...
16 CitationsSource
#1Maria Karlgren (Uppsala University)H-Index: 16
#2Anna VildhedeH-Index: 10
Last. Per ArturssonH-Index: 100
view all 8 authors...
The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug–drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics an...
230 CitationsSource
#1Tomoyuki Mizuno (Kyoto University)H-Index: 18
#2Masahide Fukudo (Kyoto University)H-Index: 17
Last. Toshiya Katsura (Kyoto University)H-Index: 51
view all 8 authors...
Summary: To elucidate the impact of genetic variations in breast cancer resistance protein (BCRP/ ABCG2) and P-glycoprotein (MDR1/ABCB1) on the pharmacokinetics of sunitinib, we carried out a pharmacogenetic study in a clinical setting and pharmacokinetic analysis using Abcg2 −/− , Abcb1a/1b −/− and Abcb1a/1b;Abcg2 −/− mice. Nineteen renal cell carcinoma patients were enrolled in this study. The plasma concentrations of sunitinib and its active metabolite were determined and the area under the c...
74 CitationsSource
#1Jamie A. Wright (Newcastle University)H-Index: 3
#2Iain S. Haslam (AstraZeneca)H-Index: 19
Last. Nicholas L. Simmons (Newcastle University)H-Index: 49
view all 4 authors...
Abstract In order to determine the capacity and regulation of the breast cancer resistance protein (BCRP)-mediated transport in intact human intestinal epithelial monolayers (Caco-2) in which multiple ABC transporters are expressed, nitrofurantoin has been used as a selective transported substrate. Nitrofurantoin transepithelial secretion was confirmed in both human BCRP and mouse bcrp-transfected MDCKII epithelia, whereas no net transepithelial secretion was observed in native or human MDR1-MDC...
18 CitationsSource
#1Jibin LiH-Index: 14
#2Donna A. VolpeH-Index: 21
Last. Ismael J. HidalgoH-Index: 1
view all 7 authors...
The objective of the present study was to determine the efflux transporters responsible for acid and lactone statin drug efflux using transporter knockdown Caco-2 cells. The bidirectional transport was determined in Caco-2 cell monolayers in which the expression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or multidrug resistance associated protein 2 (MRP2) was knocked down by transduction with lentivirus containing human transporter-targeted small hairpin RNAs (shRNAs). Ce...
74 CitationsSource
#1Pertti J. Neuvonen (HYKS: Helsinki University Central Hospital)H-Index: 105
Abstract HMG-CoA reductase inhibitors (statins) can cause skeletal muscle toxicity; the risk of toxicity is elevated by drug interactions and pharmacogenetic factors that increase the concentration of statins in the plasma. Statins are substrates for several membrane transporters that may mediate drug interactions. Inhibitors of the organic anion transporting polypeptide 1B1 can decrease the hepatic uptake of many statins, as well as the therapeutic index of these agents. Potent inhibitors of cy...
101 Citations
Cited By18
Newest
#1Yuka Takahashi (Hokkaido University)H-Index: 1
#2Katsuya Narumi (Hokkaido University)H-Index: 13
Last. Masaki Kobayashi (Hokkaido University)H-Index: 27
view all 7 authors...
Organic anion-transporting polypeptide (OATP) 2B1 plays a critical role in the intestinal absorption of substrate drugs. Apple juice reportedly interacts with OATP2B1 substrate drugs. The purpose of this study was to investigate the effect of two apple polyphenols, phloretin and phloridzin, on OATP2B1-mediated substrate transport in vitro and to evaluate the effect of phloretin on rosuvastatin pharmacokinetics in rats.In vitro studies revealed that both polyphenols inhibited OATP2B1-mediated upt...
Source
#1Panagiotis-Nikolaos Lalagkas (DUTH: Democritus University of Thrace)
#2Georgios Poulentzas (DUTH: Democritus University of Thrace)
Last. Antonios Douros (JGH: Jewish General Hospital)
view all 4 authors...
INTRODUCTION Recent case reports suggested that concomitant use of sodium-glucose co-transporter 2 (SGLT2) inhibitors with statins could lead to increased statin toxicity. We aimed to provide a comprehensive overview of the available pharmacological and clinical evidence on this potential drug-drug interaction (DDI). AREAS COVERED We searched MEDLINE PubMed until November 2020 for (i) pharmacokinetic studies on SGLT2 inhibitors, statins, and their potential interaction, and (ii) case reports and...
Source
#1Christopher Rowbottom (Biogen Idec)H-Index: 3
#2Alicia Pietrasiewics (Biogen Idec)
Last. Patrick Trapa (Biogen Idec)
view all 7 authors...
Transporters can play a key role in the absorption, distribution, metabolism, and excretion of drugs. Understanding these contributions early in drug discovery allows for more accurate projection of the clinical pharmacokinetics. One method to assess the impact of transporters in vivo involves co-dosing specific inhibitors. The objective of the present study was to optimize the dose and route of administration of a P-glycoprotein (P-gp) inhibitor, valspodar (PSC833), and a dual P-gp/breast cance...
Source
#1Eliza R. McCollH-Index: 3
#2Vessela VassilevaH-Index: 12
Last. Micheline Piquette-MillerH-Index: 52
view all 3 authors...
Source
#1Seigo Sanoh (Hiroshima University)H-Index: 19
#2Yoichi Naritomi (Astellas Pharma)H-Index: 13
Last. Shigeru Ohta (Wakayama Medical University)
view all 7 authors...
: We previously reported a prediction method for human pharmacokinetics (PK) using single species allometric scaling (SSS) and the complex Dedrick plot in chimeric mice with humanized liver to predict the total clearance (CLt), distribution volumes in steady state (Vdss) and plasma concentration-time profiles of several drugs metabolized by cytochrome P450 (P450) and non-P450 enzymes. In the present study, we examined eight compounds (bosentan, cerivastatin, fluvastatin, pitavastatin, pravastati...
Source
#1Iichiro Kawahara (Kyoto Pharmaceutical University)H-Index: 3
#2Satoyo Nishikawa (Kyoto Pharmaceutical University)H-Index: 2
Last. Takuya Fujita (Rits: Ritsumeikan University)H-Index: 59
view all 5 authors...
Prediction of the intestinal absorption of new chemical entities (NCEs) is still difficult, in part because drug efflux transporters, including breast cancer resistance protein (BCRP) and P‐glycoprotein (P‐gp), restrict their intestinal permeability. We have demonstrated that the absorptive quotient (AQ) obtained from the in vitro Caco‐2 permeability study would be a valuable parameter for estimating the impact of BCRP on the intestinal absorption of drugs. In this study, in order to assess the ...
2 CitationsSource
#1Luping Zhou (CSU: Central South University)H-Index: 6
#2Lulu Chen (CSU: Central South University)H-Index: 6
Last. Dong-Sheng Ouyang (CSU: Central South University)H-Index: 23
view all 12 authors...
Abstract Background Ginsenoside compound K (CK) is a promising drug candidate for rheumatoid arthritis. This study examined the impact of polymorphisms in NR1I2 , adenosine triphosphate–binding cassette (ABC) transporter genes on the pharmacokinetics of CK in healthy Chinese individuals. Methods Forty-two targeted variants in seven genes were genotyped in 54 participants using Sequenom MassARRAY system to investigate their association with major pharmacokinetic parameters of CK and its metabolit...
6 CitationsSource
#1Jie Yang (Tottori University)H-Index: 2
#2Junichi HasegawaH-Index: 21
Last. Akiko Matsuda (Nara Medical University)H-Index: 1
view all 6 authors...
Background Tanjin is an herbal medicine made from the root of salvia miltiorrhiza. It is predominantly given to arteriosclerotic patients as a supplement to ameliorate the clinical symptoms of cardiovascular diseases. In China, tanjin is used frequently in combination treatment for hypercholesterolemia. Thus, there is a high probability of combination of tanjin and statins in these arteriosclerotic patients. This study investigated the interaction between tanjin and rosuvastatin.
4 CitationsSource
#1Donna A. Volpe (CDER: Center for Drug Evaluation and Research)H-Index: 21
#2Hisham Qosa (CDER: Center for Drug Evaluation and Research)H-Index: 14
ABSTRACTIntroduction: Given that membrane efflux transporters can influence a drug’s pharmacokinetics, efficacy and safety, identifying potential substrates and inhibitors of these transporters is a critical element in the drug discovery and development process. Additionally, it is important to predict the inhibition potential of new drugs to avoid clinically significant drug interactions. The goal of preclinical studies is to characterize a new drug as a substrate or inhibitor of efflux transpo...
1 CitationsSource
#1Tsuyoshi Karibe (Daiichi Sankyo)H-Index: 4
#2Tomoki Imaoka (Daiichi Sankyo)H-Index: 6
Last. Osamu Ando (Daiichi Sankyo)H-Index: 16
view all 4 authors...
To estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (BCRP), in vivo approaches in nonclinical settings are desired in drug development. Clinical observation has identified curcumin as a promising candidate for in vivo selective BCRP inhibition, in addition to several well known inhibitors, such as lapatinib and pantoprazole. This study aimed to confirm the inhibitory efficacy of curcumin on gastrointestinal BCRP function in cynomolgus monkeys and to...
12 CitationsSource