Effects of renal failure on drug transport and metabolism

Sun, Hong; Frassetto, Lynda; Benet, Leslie Z.

doi:10.1016/j.pharmthera.2005.05.010

Cited by 246 publications

(229 citation statements)

References 94 publications

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“…P-gp is the bestcharacterized transporter, originally discovered for its overexpression in drug-resistant tumor cells, but now recognized as a crucial component of tissues with a barrier function. 80 The efflux pump has a preference for uncharged and cationic compounds and was found to be differentially regulated in CKD rats, 81 but evidence of its involvement in renal uremic toxin excretion is lacking. The MRPs mediate the transport of a wide scale of organic anionic compounds and their metabolites, including glucuronide, glutathione, and sulfate conjugates.…”

Section: Urinary Efflux Transporters For Uremic Toxinsmentioning

confidence: 99%

“…81,109 During the process of drug metabolism, three phases can be distinguished: phase I reactions, mainly occurring in the liver, are oxidation reactions mediated by cytochrome P450 (CYP) enzymes. Phase II reactions are conjugation reactions encompassing acetylation, sulfation, and glucuronidation, which primarily take place in the liver, kidney, and gastrointestinal tract.…”

Section: Intracellular Fate Of Uremic Toxinsmentioning

confidence: 99%

See 1 more Smart Citation

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Masereeuw

Mutsaers

Toyohara³

et al. 2014

Seminars in Nephrology

133

122

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This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited.

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Section: Urinary Efflux Transporters For Uremic Toxinsmentioning

confidence: 99%

Section: Intracellular Fate Of Uremic Toxinsmentioning

confidence: 99%

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Masereeuw

Mutsaers

Toyohara³

et al. 2014

Seminars in Nephrology

133

122

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“…This oversight is significant because evidence increasingly indicates that hepatic drug metabolism and transport are reduced in patients with [14][15][16][17][18][19][20][21][22][25][26][27][28]30). Consequently, administering the full dose of a hepatically metabolized medication may place an ESRD patient at similar risk for an adverse drug event as administering the full dose of a renally eliminated medication.Experimental evidence suggests multiple mechanisms by which uremic solutes might influence hepatic drug disposition (20,25). Studies from the Pichette laboratory demonstrated that the activity and expression of cytochrome P-450 (CYP450) was reduced in the 5/6th nephrectomy (5/6N) rat model of chronic renal failure (6, 10, 11).…”

mentioning

confidence: 99%

“…This has likely improved the safety of these medications for the ESRD population, yet it remains an incomplete approach, since it does not include the hepatically metabolized medications. This oversight is significant because evidence increasingly indicates that hepatic drug metabolism and transport are reduced in patients with [14][15][16][17][18][19][20][21][22][25][26][27][28]30). Consequently, administering the full dose of a hepatically metabolized medication may place an ESRD patient at similar risk for an adverse drug event as administering the full dose of a renally eliminated medication.…”

mentioning

confidence: 99%

Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

Ryan

Dunn

Decker

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Ryan JC, Dunn KW, Decker BS. Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver. Am J Physiol Regul Integr Comp Physiol 307: R1488 -R1492, 2014. First published October 22, 2014 doi:10.1152/ajpregu.00371.2014.-Clinical studies indicate that hepatic drug transport may be altered in chronic kidney disease (CKD). Uremic solutes associated with CKD have been found to alter the expression and/or activity of hepatocyte transporters in experimental animals and in cultured cells. However, given the complexity and adaptability of hepatic transport, it is not clear whether these changes translate into significant alterations in hepatic transport in vivo. To directly measure the effect of CKD on hepatocyte transport in vivo, we conducted quantitative intravital microscopy of transport of the fluorescent organic anion fluorescein in the livers of rats following 5/6th nephrectomy, an established model of CKD. Our quantitative analysis of fluorescein transport showed that the rate of hepatocyte uptake was reduced by ϳ20% in 5/6th nephrectomized rats, consistent with previous observations of Oatp downregulation. However, the overall rate of transport into bile canaliculi was unaffected, suggesting compensatory changes in Mrp2-mediated secretion. Our study suggests that uremia resulting from 5/6th nephrectomy does not significantly impact the overall hepatic clearance of an Oatp substrate. chronic kidney disease; uremia; cytochrome P-450; hepatic transport; Mrp2; Oatp; sodium fluorescein PATIENTS WITH END-STAGE RENAL disease (ESRD) receiving dialysis take on average 12 medications to manage the complications of their renal failure and their comorbid disease, which places them at a substantial risk for adverse drug events (8,12,13). Currently, modifications in drug dosing to improve safety for ESRD patients have largely been confined to those medications excreted renally. This has likely improved the safety of these medications for the ESRD population, yet it remains an incomplete approach, since it does not include the hepatically metabolized medications. This oversight is significant because evidence increasingly indicates that hepatic drug metabolism and transport are reduced in patients with [14][15][16][17][18][19][20][21][22][25][26][27][28]30). Consequently, administering the full dose of a hepatically metabolized medication may place an ESRD patient at similar risk for an adverse drug event as administering the full dose of a renally eliminated medication.Experimental evidence suggests multiple mechanisms by which uremic solutes might influence hepatic drug disposition (20,25). Studies from the Pichette laboratory demonstrated that the activity and expression of cytochrome P-450 (CYP450) was reduced in the 5/6th nephrectomy (5/6N) rat model of chronic renal failure (6, 10, 11). Their work elucidated a direct role for uremic solutes with the observation that CYP450 activity and expression were reduced in primary rat hepatocytes incubated wit...

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“…The polarity of the drug is an important factor in renal elimination, since this characteristic determines the solubility in water. Most drugs are rendered more water soluble when they are converted to metabolites, resulting in increased elimination by specialized transporters found in renal tissue [66,67]. Some drugs can also be absorbed by the lungs and eliminated via exhalation.…”

Section: Introductionmentioning

confidence: 99%

Biomedical Technologies for In Vitro Screening and Controlled Delivery of Neuroactive Compounds

Frampton¹,

Shuler²,

Shain³

et al. 2008

CNSAMC

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Cell culture models can provide information pertaining to the effective dose, toxiciology, and kinetics, for a variety of neuroactive compounds. However, many in vitro models fail to adequately predict how such compounds will perform in a living organism. At the systems level, interactions between organs can dramatically affect the properties of a compound by alteration of its biological activity or by elimination of it from the body. At the tissue level, interaction between cell types can alter the transport properties of a particular compound, or can buffer its effects on target cells by uptake, processing, or changes in chemical signaling between cells. In any given tissue, cells exist in a three-dimensional environment bounded on all sides by other cells and components of the extracellular matrix, providing kinetics that are dramatically different from the kinetics in traditional two-dimensional cell culture systems. Cell culture analogs are currently being developed to better model the complex transport and processing that occur prior to drug uptake in the CNS, and to predict blood-brain barrier permeability. These approaches utilize microfluidics, hydrogel matrices, and a variety of cell types (including lung epithelial cells, hepatocytes, adipocytes, glial cells, and neurons) to more accurately model drug transport and biological activity. Similar strategies are also being used to control both the spatial and temporal release of therapeutic compounds for targeted treatment of CNS disease.

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Effects of renal failure on drug transport and metabolism

Cited by 246 publications

References 94 publications

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

Biomedical Technologies for In Vitro Screening and Controlled Delivery of Neuroactive Compounds

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