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The impact of Organic Anion-Transporting Polypeptides (OATPs) on disposition and toxicity of antitumor drugs: Insights from knockout and humanized mice.
- Source :
-
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy [Drug Resist Updat] 2016 Jul; Vol. 27, pp. 72-88. Date of Electronic Publication: 2016 Jun 25. - Publication Year :
- 2016
-
Abstract
- It is now widely accepted that organic anion-transporting polypeptides (OATPs), especially members of the OATP1A/1B family, can have a major impact on the disposition and elimination of a variety of endogenous molecules and drugs. Owing to their prominent expression in the sinusoidal plasma membrane of hepatocytes, OATP1B1 and OATP1B3 play key roles in the hepatic uptake and plasma clearance of a multitude of structurally diverse anti-cancer and other drugs. Here, we present a thorough assessment of the currently available OATP1A and OATP1B knockout and transgenic mouse models as key tools to study OATP functions in vivo. We discuss recent studies using these models demonstrating the importance of OATPs, primarily in the plasma and hepatic clearance of anticancer drugs such as taxanes, irinotecan/SN-38, methotrexate, doxorubicin, and platinum compounds. We further discuss recent work on OATP-mediated drug-drug interactions in these mouse models, as well as on the role of OATP1A/1B proteins in the phenomenon of hepatocyte hopping, an efficient and flexible way of liver detoxification for both endogenous and exogenous substrates. Interestingly, glucuronide conjugates of both the heme breakdown product bilirubin and the protein tyrosine kinase-targeted anticancer drug sorafenib are strongly affected by this process. The clinical relevance of variation in OATP1A/1B activity in patients has been previously revealed by the effects of polymorphic variants and drug-drug interactions on drug toxicity. The development of in vivo tools to study OATP1A/1B functions has greatly advanced our mechanistic understanding of their functional role in drug pharmacokinetics, and their implications for therapeutic efficacy and toxic side effects of anticancer and other drug treatments.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents pharmacology
Camptothecin analogs & derivatives
Camptothecin pharmacokinetics
Camptothecin pharmacology
Camptothecin toxicity
Doxorubicin pharmacokinetics
Doxorubicin pharmacology
Doxorubicin toxicity
Drug Interactions
Gene Expression
Hepatocytes drug effects
Hepatocytes metabolism
Hepatocytes pathology
Humans
Irinotecan
Liver drug effects
Liver metabolism
Liver pathology
Liver-Specific Organic Anion Transporter 1 metabolism
Methotrexate pharmacokinetics
Methotrexate pharmacology
Methotrexate toxicity
Mice
Mice, Transgenic
Neoplasms drug therapy
Neoplasms genetics
Neoplasms pathology
Niacinamide analogs & derivatives
Niacinamide pharmacokinetics
Niacinamide pharmacology
Niacinamide toxicity
Organic Cation Transport Proteins deficiency
Phenylurea Compounds pharmacokinetics
Phenylurea Compounds pharmacology
Phenylurea Compounds toxicity
Platinum Compounds pharmacokinetics
Platinum Compounds pharmacology
Platinum Compounds toxicity
Sorafenib
Taxoids pharmacokinetics
Taxoids pharmacology
Taxoids toxicity
Antineoplastic Agents toxicity
Inactivation, Metabolic genetics
Liver-Specific Organic Anion Transporter 1 genetics
Neoplasms metabolism
Organic Cation Transport Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1532-2084
- Volume :
- 27
- Database :
- MEDLINE
- Journal :
- Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 27449599
- Full Text :
- https://doi.org/10.1016/j.drup.2016.06.005