Involvement of Transporters in the Hepatic Uptake and Biliary Excretion of Valsartan, a Selective Antagonist of the Angiotensin Ii At1-Receptor, in Humans

Yamashiro, Wakaba; Maeda, Kazuya; Hirouchi, Masakazu; Adachi, Yasuhisa; Hu, Zhuohan; Sugiyama, Yuichi

doi:10.1124/dmd.105.008938

Cited by 184 publications

(107 citation statements)

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“…Recently, it was recognized that a broad variety of drugs, including many cardiovascular drugs such as statins and angiotensin II-receptor antagonists, is transported through biological membranes via specific transport proteins (15,(22)(23)(24). For example, the efflux transporter Pglycoprotein, which translocates its substrates from the inside of the cell to the outside (e.g., from the hepatocyte into bile) is a major determinant of drug effects (1).…”

Section: Discussionmentioning

confidence: 99%

Interaction of Oral Antidiabetic Drugs With Hepatic Uptake Transporters

et al. 2008

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OBJECTIVE-The uptake of drugs into hepatocytes is a key determinant for hepatic metabolism, intrahepatic action, their subsequent systemic plasma concentrations, and extrahepatic actions. In vitro and in vivo studies indicate that many drugs used for treatment of cardiovascular diseases (e.g., oral antidiabetic drugs, statins) are taken up into hepatocytes by distinct organic anion transporters (organic anion transporting polypeptides [OATPs]; gene symbol SLCO/SLC21) or organic cation transporters (OCTs; gene symbol SLC22). Because most patients with type 2 diabetes receive more than one drug and inhibition of drug transporters has been recognized as a new mechanism underlying drug-drug interactions, we tested the hypothesis of whether oral antidiabetic drugs can inhibit the transport mediated by hepatic uptake transporters.RESEARCH DESIGN AND METHODS-Using stably transfected cell systems recombinantly expressing the uptake transporters OATP1B1, OATP1B3, OATP2B1, or OCT1, we analyzed whether the antidiabetic drugs repaglinide, rosiglitazone, or metformin influence the transport of substrates and drugs (for OATPs, sulfobromophthalein [BSP] and pravastatin; for OCT1, 1-methyl-4-phenylpyridinium [MPP ϩ ] and metformin).RESULTS-Metformin did not inhibit the uptake of OATP and OCT1 substrates. However, OATP-mediated BSP and pravastatin uptake and OCT1-mediated MPP ϩ and metformin uptake were significantly inhibited by repaglinide (half-maximal inhibitory concentration [IC 50 ] 1.6 -5.6 mol/l) and rosiglitazone (IC 50 5.2-30.4 mol/l).CONCLUSIONS-These in vitro results demonstrate that alterations of uptake transporter function by oral antidiabetic drugs have to be considered as potential mechanisms underlying drug-drug interactions.

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Section: Discussionmentioning

confidence: 99%

Interaction of Oral Antidiabetic Drugs With Hepatic Uptake Transporters

et al. 2008

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“…The search was extended to other sources for biliarily eliminated drugs (44)(45)(46)(47)(48)(49)(50)(51). Drugs were considered nonsubstrates for efflux ratios<1.8 and substrates if the efflux ratio was>2.2.…”

Section: Additional Considerationsmentioning

confidence: 99%

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Hosey-Cojocari

Broccatelli

Benet

2014

AAPS J

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Abstract. Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposition Classification System (BDDCS) characterizes significant routes of drug elimination, identifies potential transporter effects, and is useful in understanding drug-drug interactions. Class 1 and 2 drugs are primarily eliminated in humans via metabolism and will not exhibit significant biliary excretion of parent compound. In contrast, class 3 and 4 drugs are primarily excreted unchanged in the urine or bile. Here, we characterize the significant elimination route of 105 orally administered class 3 and 4 drugs. We introduce and validate a novel model, predicting significant biliary elimination using a simple classification scheme. The model is accurate for 83% of 30 drugs collected after model development. The model corroborates the observation that biliarily eliminated drugs have high molecular weights, while demonstrating the necessity of considering route of administration and extent of metabolism when predicting biliary excretion. Interestingly, a predictor of potential metabolism significantly improves predictions of major elimination routes of poorly metabolized drugs. This model successfully predicts the major elimination route for poorly permeable/poorly metabolized drugs and may be applied prior to human dosing.

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“…In our in vitro uptake assay using a gene expression system, valsartan is a substrate of both OATP1B1 and OATP1B3 and our RAF method revealed that the relative contribution of OATP1B1 and OATP1B3 to its hepatic uptake is almost the same, though the result shows a large variation depending on the batch of human hepatocytes. 12) On the other hand, interestingly, telmisartan is recognized only by OATP1B3, but not OATP1B1. 13) To further confirm this result, we created a third approach using an isoform-selective inhibitor 13) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

Maeda

2015

Biological & Pharmaceutical Bulletin

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119

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Nobody doubts the importance of organic anion transporting polypeptide (OATP)1B1 and 1B3 in the clinical pharmacokinetics of substrate drugs. Based on the theory of pharmacokinetics, even if a drug is eliminated from the body by extensive metabolism, the rate-determining process of the hepatic intrinsic clearance of OATP substrates is often hepatic uptake. Because of their broad substrate specificities, once the functions of OATP1B1 or OATP1B3 are altered by several kinds of special occasions such as drug-drug interactions (DDI) and genetic polymorphisms of transporter genes, the hepatic clearance of many kinds of structurally-unrelated drugs is expected to be changed. In some cases, these alterations of pharmacokinetics lead to modified pharmacological effects and adverse reactions such as statin-induced myotoxicity and the glucose-lowering effect of anti-diabetes drugs. Thus, appropriate methods with which to quantitatively predict the changes in plasma and tissue concentrations of drugs are needed in the process of drug development. As for DDI, a static model that takes into consideration of the theoretically-maximum unbound inhibitor concentration is often used for the sensitive detection of possible DDI risks and this method has been adopted in several regulatory guidance/guidelines on DDI. Regarding genetic polymorphisms, the effects of SLCO1B1 c.388A>G and c.521T>C on the pharmacokinetics of substrate drugs have been extensively investigated. Even though there are some discrepancies, c.521T>C generally decreased hepatic uptake activity, while c.388A>G tended to slightly increase it. This article briefly summarizes the current status of research on hepatic OATP1B1 and OATP1B3 and the clinical significance of their functions.

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Involvement of Transporters in the Hepatic Uptake and Biliary Excretion of Valsartan, a Selective Antagonist of the Angiotensin Ii At1-Receptor, in Humans

Cited by 184 publications

References 25 publications

Interaction of Oral Antidiabetic Drugs With Hepatic Uptake Transporters

Interaction of Oral Antidiabetic Drugs With Hepatic Uptake Transporters

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

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