ArticleDrug metabolism and disposition: the biological fate of chemicals2014
Utility of Oatp1a/1b-knockout and OATP1B1/3-humanized mice in the study of OATP-mediated pharmacokinetics and tissue distribution: case studies with pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 92 citations in OpenAlex.
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- Regulation of hepatic organic anion transporting polypeptide 1B-type transport function by the protein kinase LYN.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- OATP1B-type Transport Function Is a Determinant of Aromatase Inhibitor-Associated Arthralgia Susceptibility.Cancer research communications · 2025Article
- Rifampin- and Silymarin-Mediated Pharmacokinetic Interactions of Exogenous and Endogenous Substrates in a Transgenic OATP1B Mouse Model.Molecular pharmaceutics · 2024Article
- Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice.Drug metabolism and disposition: the biological fate of chemicals · 2024Article
- Construction and characterization of a humanizedActa pharmaceutica Sinica. B · 2024Article
- Mechanistic Static Model based Prediction of Transporter Substrate Drug-Drug Interactions Utilizing Atorvastatin and Rifampicin.Pharmaceutical research · 2023Article
- Pharmacokinetic and pharmacodynamic drug-drug interaction of Nomilin with atorvastatin in hyperlipidemic mice.Heliyon · 2023Article
- Evaluation of the Effects of Repeat-Dose Dabrafenib on the Single-Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate).Clinical pharmacology in drug development · 2021Article
- Comparison of Hepatic Transporter Tissue Expression in Rodents and Interspecies Hepatic OCT1 Activity.The AAPS journal · 2021Article
- Transport Properties of Statins by Organic Anion Transporting Polypeptide 1A2 and Regulation by Transforming Growth Factor-The Journal of pharmacology and experimental therapeutics · 2021Article
- Differential Detergent Fractionation of Membrane Protein From Small Samples of Hepatocytes and Liver Tissue for Quantitative Proteomic Analysis of Drug Metabolizing Enzymes and Transporters.Journal of pharmaceutical sciences · 2021Article
- Scutellarin is Highly Likely to be Responsible for Drug-Drug Interactions Mediated by Hepatic Organic Anion-Transporting Polypeptide1B3.Pharmaceutical research · 2020Article
- A hybrid model to evaluate the impact of active uptake transport on hepatic distribution of atorvastatin in rats.Xenobiotica; the fate of foreign compounds in biological systems · 2020Article
- Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- PGC-1α plays a pivotal role in simvastatin-induced exercise impairment in mice.Acta physiologica (Oxford, England) · 2020Article
- Pharmacokinetics of Organic Cation Transporter 1 (OCT1) Substrates in Oct1/2 Knockout Mice and Species Difference in Hepatic OCT1-Mediated Uptake.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Brain Delivery of a Potent Opioid Receptor Agonist, Biphalin during Ischemic Stroke: Role of Organic Anion Transporting Polypeptide (OATP).Pharmaceutics · 2019Article
- Neurovascular unit transport responses to ischemia and common coexisting conditions: smoking and diabetes.American journal of physiology. Cell physiology · 2019Review
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Authors and funding
7 authors at 2 institutions in 1 country.
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Abstract
Although organic anion transporting polypeptide (OATP)-mediated hepatic uptake is generally conserved between rodents and humans at a gross pharmacokinetic level, the presence of three major hepatic OATPs with broad overlap in substrate and inhibitor affinity, and absence of rodent-human orthologs preclude clinical translation of single-gene knockout/knockin findings. At present, changes in pharmacokinetics and tissue distribution of pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein were studied in oatp1a/1b-knockout mice lacking the three major hepatic oatp isoforms, and in knockout mice with liver-specific knockin of human OATP1B1 or OATP1B3. Relative to wild-type controls, oatp1a/1b-knockout mice exhibited 1.6- to 19-fold increased intravenous and 2.1- to 115-fold increased oral drug exposure, due to 33%-75% decreased clearance, 14%-60% decreased volume of distribution, and ≤74-fold increased oral bioavailability, with the magnitude of change depending on the contribution of oatp1a/1b to pharmacokinetics. Hepatic drug distribution was 4.2- to 196-fold lower in oatp1a/1b-knockout mice; distributional attenuation was less notable in kidney, brain, cardiac, and skeletal muscle. Knockin of OATP1B1 or OATP1B3 partially restored control clearance, volume, and bioavailability values (24%-142% increase, ≤47% increase, and ≤77% decrease vs. knockout, respectively), such that knockin pharmacokinetic profiles were positioned between knockout and wild-type mice. Consistent with liver-specific humanization, only hepatic drug distribution was partially restored (1.3- to 6.5-fold increase vs. knockout). Exposure and liver distribution changes in OATP1B1-humanized versus knockout mice predicted the clinical impact of OATP1B1 on oral exposure and contribution to human hepatic uptake of statins within 1.7-fold, but only after correcting for human/humanized mouse liver relative protein expression factor (OATP1B1 = 2.2, OATP1B3 = 0.30).
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