Organic Cation Transporter-Mediated Renal Secretion of Ipratropium and Tiotropium in Rats and Humans

Nakanishi, Takeo; Haruta, Tsunemitsu; Shirasaka, Yoshiyuki; Tamai, Ikumi

doi:10.1124/dmd.110.035402

Cited by 39 publications

(21 citation statements)

References 31 publications

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“…However, major anticholinergics, ipratropium bromide (IPR) and tiotropium bromide, which are chemically related to atropine,1 are highly hydrophilic and unlikely to cross the plasma membrane by diffusion. Early pharmacokinetic studies indicated that their renal clearances are several fold greater than the glomerular filtration rate,2,3 and we subsequently demonstrated that these anticholinergics are recognized and transported by human organic cation/carnitine transporters (OCTN1/ SLC22A4 and OCTN2/ SLC22A5 ),4 as well as human and rat organic cation transporters (OCT1/ SLC22A1 and OCT2/ SLC22A2 ), indicating that vectorial transport mediated by these organic cation transporters plays a key role in efficient renal secretion of these compounds 5…”

Section: Introductionsupporting

confidence: 51%

Reply to Improved Survival With Adjuvant External‐Beam Radiation Therapy in Lymph Node‐Negative Pancreatic Cancer

Artinyan

Kim

2008

Cancer

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Section: Introductionsupporting

confidence: 51%

Reply to Improved Survival With Adjuvant External‐Beam Radiation Therapy in Lymph Node‐Negative Pancreatic Cancer

Artinyan

Kim

2008

Cancer

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“…This clearly does not impede their usefulness as inhaled drugs. However, the fact that both are substrates of organic cation transporter proteins (OCTs) may facilitate their transport through the lungs since this family of drug transporters is expressed in the lung [32,33]. Further work is required in the future to fully understand if and how absorptive drug transporters in the lung can be exploited to enhance inhaled drug delivery.…”

Section: Absorptionmentioning

confidence: 99%

Optimisation of DMPK by the Inhaled Route: Challenges and Approaches

Cooper¹,

Ferguson²,

Grime³

2012

CDM

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The renewed interest in inhalation delivery over recent years has led to an expansion in the understanding of lung pharmacokinetics. Historically optimisation of inhaled drugs focused largely on development of material properties, consistent with achieving a good lung deposition, alongside demonstrating appropriate in vivo efficacy with little understanding of the relationship to pharmacokinetics in the lung. Recent efforts have led to an increased understanding of lung concentrations and how to maximise exposure in order to achieve the desired pharmacological response at a dose consistent with development of an inhaled product. Although there is a prerequisite for excellent potency in inhalation delivery, it is essential that this be combined with pharmacokinetic properties that allow sufficient free concentration at the effect site in lung to exert the pharmacological response for an appropriate dosing interval. Increases in basicity, polarity and/or decreases in aqueous solubility can extend pharmacokinetic duration and assist in finding the right balance between lung and systemic exposure. Current evidence suggests there are similarities in lung retention in rat and dog and that animal lung concentration data can enable pharmacokinetic-pharmacodynamic relationships to be derived thus providing more confidence in the requirements for man. Although inhaled delivery is challenging from a pharmacokinetic point of view, direct evaluation of exposure in the target organ has enabled further understanding of the drivers for drug disposition and highlighted the need for further development of predictive lung pharmacokinetic tools in the future.

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“…After washing and removal of unattached cells, leaving a semiconfluent cell monolayer (.90% confluent), uptakes were performed at 1 mM substrate concentration in KHL. The activities of uptake transporters were tested with several well characterized substrates: rosuvastatin (AstraZeneca), OATPs (Ho et al, 2006); fexofenadine, OATPs (Cvetkovic et al, 1999); ipratropium, OCTs (Nakanishi et al, 2011); and taurocholate, NTCP (Ozawa et al, 2004). Rosuvastatin is also an NTCP substrate in human but not rat cells (Ho et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

The Impact of Solute Carrier (SLC) Drug Uptake Transporter Loss in Human and Rat Cryopreserved Hepatocytes on Clearance Predictions

et al. 2014

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Cryopreserved hepatocytes are often used as a convenient tool in studies of hepatic drug metabolism and disposition. In this study, the expression and activity of drug transporters in human and rat fresh and cryopreserved hepatocytes was investigated. In human cryopreserved hepatocytes, Western blot analysis indicated that protein expression of the drug uptake transporters [human Na + -taurocholate cotransporting polypeptide (NTCP), human organic anion transporting polypeptides (OATPs), human organic anion transporters, and human organic cation transporters (OCTs)] was considerably reduced compared with liver tissue. In rat cryopreserved cells, the same trend was observed but to a lesser extent. Several rat transporters were reduced as a result of both isolation and cryopreservation procedures. Immunofluorescence showed that a large portion of remaining human OATP1B1 and OATP1B3 transporters were internalized in human cryopreserved hepatocytes. Measuring uptake activity using known substrates of OATPs, OCTs, and NTCP showed decreased activity in cryopreserved as compared with fresh hepatocytes in both species. The reduced uptake in cryopreserved hepatocytes limited the in vitro metabolism of several AstraZeneca compounds. A retrospective analysis of clearance predictions of AstraZeneca compounds suggested systematic lower clearance predicted using metabolic stability data from human cryopreserved hepatocytes compared with human liver microsomes. This observation is consistent with a loss of drug uptake transporters in cryopreserved hepatocytes. In contrast, the predicted metabolic clearance from fresh rat hepatocytes was consistently higher than those predicted from liver microsomes, consistent with retention of uptake transporters. The uptake transporters, which are decreased in cryopreserved hepatocytes, may be rate-limiting for the metabolism of the compounds and thus be one explanation for underpredictions of in vivo metabolic clearance from cryopreserved hepatocytes.

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Organic Cation Transporter-Mediated Renal Secretion of Ipratropium and Tiotropium in Rats and Humans

Cited by 39 publications

References 31 publications

Reply to Improved Survival With Adjuvant External‐Beam Radiation Therapy in Lymph Node‐Negative Pancreatic Cancer

Reply to Improved Survival With Adjuvant External‐Beam Radiation Therapy in Lymph Node‐Negative Pancreatic Cancer

Optimisation of DMPK by the Inhaled Route: Challenges and Approaches

The Impact of Solute Carrier (SLC) Drug Uptake Transporter Loss in Human and Rat Cryopreserved Hepatocytes on Clearance Predictions

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