Article Figures & Data
Figures
- Fig. 1.
Alterations in hepatic drug disposition in patients with kidney disease. Plasma concentrations of uremic toxins and inflammatory cytokines are elevated in kidney dysfunction. Uremic toxins can inhibit the expression of OATs and OCT2 in the kidneys. Uremic toxins can also inhibit and downregulate hepatic pharmacokinetic proteins, including OATP1B and cytochrome P450, in the liver. Uremic toxins can activate macrophages, resulting in the release of inflammatory cytokines that can modulate the hepatic pharmacokinetic proteins. ABC, ATP-binding cassette.
Tables
Uremic toxins Total Cmax Unbound Cmax OAT1 IC50 OAT3 IC50 OATP1B1 IC50 2-Nonenala 727 µM (Duranton et al., 2012) 0.7 µM (Hsueh et al., 2016) IC50: 19 µM for 6-CF uptake (Hsueh et al., 2016) 60 µM for 6-CF uptake (Hsueh et al., 2016) N/A 4-Decenala 650 µM (Duranton et al., 2012) 0.7 µM (Hsueh et al., 2016) IC50: 38 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 53 µM for 6-CF uptake (Hsueh et al., 2016) N/A 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) 81.1 µM (Fujita et al., 2014) N/A IC50: 79 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 28 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 158 µM for SN38 uptake (Fujita et al., 2014) Creatinine N/A 1.2 mM (Hsueh et al., 2016) IC50: 14 mM for 6-CF uptake (Hsueh et al., 2016) IC50: 40 mM for 6-CF uptake (Hsueh et al., 2016) IC50: > 10 mM for E13S uptake (Sato et al., 2014) Hippuric acid 398 µM (Duranton et al., 2012) 231 (Duranton et al., 2012) IC50: 31 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 41 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 6.71 mM for SN38 uptake (Fujita et al., 2014) 6-Hydroxyindole 0.227 µM (Masuo et al., 2020) N/A N/A N/A IC50: 16.7 (coincubation)
IC50: 12.1 (pre- and coincubation) (Masuo et al., 2020)Indole 3-acetic acid 11.6 µM (Duranton et al., 2012) 2.11 (Duranton et al., 2012) IC50: 140 µM for 6-CF uptake (Hsueh et al., 2016) 38% inhibition for 6-CF uptake by 250 µM (Hsueh et al., 2016) >3 mM for SN38 uptake (Fujita et al., 2014)
194 µM for SN38 uptake (Katsube et al., 2017)Indoxyl sulfate 109 µM (Duranton et al., 2012) 15.1 µM (Duranton et al., 2012) IC50: 110 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 270 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 2.29 mM for SN38 uptake (Fujita et al., 2014) Indoxyl-β-D-glucuronidea 9.49 µM (Duranton et al., 2012) N/A N/A IC50: 670 µM for 6-CF uptake (Hsueh et al., 2016) N/A Kynurenic acida 0.799 µM (Duranton et al., 2012) N/A IC50: 34 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 23 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 180 µM for E13S uptake (Sato et al., 2014) N2,N2-Dimethylguanosine N/A 1.3 µM (Hsueh et al., 2016) no inhibition for 6-CF uptake by 140 µM (Hsueh et al., 2016) IC50: 140 µM for 6-CF uptake (Hsueh et al., 2016) N/A Nonanal 0.485 µM (Duranton et al., 2012) 0.5 µM (Hsueh et al., 2016) IC50: 22 µM for 6-CF uptake (Hsueh et al., 2016) 42% inhibition for 6-CF uptake by 50 µM (Hsueh et al., 2016) N/A p-Cresol N/A N/A N/A N/A IC50: 4.6 mM for E13S uptake (Sato et al., 2014) p-Cresyl sulfate N/A 211 µM (Hsueh et al., 2016) IC50: 210 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 200 µM for 6-CF uptake (Hsueh et al., 2016) 47% inhibition by 1 mM (Masuo et al., 2020) Phenol 59 µM (Hsueh et al., 2016) N/A 31% Inhibition for 6-CF uptake by 6.4 mM (Hsueh et al., 2016) IC50: 3.1 mM for 6-CF uptake (Hsueh et al., 2016) N/A Phenylacetic acid N/A 3.5 mM (Hsueh et al., 2016) IC50: 540 µM for 6-CF uptake (Hsueh et al., 2016) IC50: 1.3 mM for 6-CF uptake (Hsueh et al., 2016) N/A Uric acid 383 µM (Duranton et al., 2012) 500 µM (Hsueh et al., 2016) IC50: 2.2 mM for 6-CF uptake (Hsueh et al., 2016) IC50: 670 µM for 6-CF uptake (Hsueh et al., 2016) N/A 6-CF, 6-carboxyfluorescein; E3S, estrone-3-sulfate; N/A, not available.
aHighest concentrations of Cmax and unbound Cmax for uremic toxins.
- TABLE 2
Effects of inflammatory cytokines on the expression levels of drug-metabolizing enzymes and transporters in primary cultured human hepatocytes
IL-1β IL-2 IL-6 IFNγ TGFβ TNFα NTCP ↓ (mRNA) (Le Vee et al., 2008)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA, protein) (Le Vee et al., 2009)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Le Vee et al., 2011) ↓ (mRNA, protein) (Le Vee et al., 2009) OAT2 → (mRNA) (Nguyen et al., 2015) ↓ (mRNA) (Le Vee et al., 2009)
→ (mRNA) (Nguyen et al., 2015)→ (mRNA) (Le Vee et al., 2011) ↓ (mRNA) (Le Vee et al., 2009) OATP1B1 ↓ (mRNA, protein) (Le Vee et al., 2008)
↓ (mRNA, protein) (Le Vee et al., 2009)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA, protein) (Le Vee et al., 2009)
→ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Le Vee et al., 2011) ↓ (mRNA, protein) (Le Vee et al., 2009) OATP1B3 ↓ (mRNA) (Le Vee et al., 2008)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Le Vee et al., 2009)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Le Vee et al., 2011) ↓ (mRNA) (Le Vee et al., 2009) OATP2B1 ↓ (mRNA) (Le Vee et al., 2008)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Le Vee et al., 2009)
→ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Le Vee et al., 2011) ↓ (mRNA) (Le Vee et al., 2009) OCT1 ↓ (mRNA) (Nguyen et al., 2015) ↓ (mRNA) (Le Vee et al., 2009)
↓ (mRNA) (Nguyen et al., 2015)→ (mRNA) (Le Vee et al., 2011) ↓ (mRNA) (Le Vee et al., 2009) MRP2 ↓ (mRNA) (Le Vee et al., 2008)
↓ (mRNA, protein) (Diao et al., 2010)↓ (mRNA, protein) (Le Vee et al., 2009)
↓ (mRNA, protein) (Diao et al., 2010)
→ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Le Vee et al., 2011) → (mRNA) (Le Vee et al., 2009)
↓ (mRNA, protein) (Diao et al., 2010)MRP3 ↓ (mRNA) (Le Vee et al., 2008)
→ (mRNA) (Nguyen et al., 2015)↓ (mRNA), ↑ (protein) (Le Vee et al., 2009)
→ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Le Vee et al., 2011) → (mRNA), ↑ (protein) (Le Vee et al., 2009) MRP4 ↓ (mRNA) (Le Vee et al., 2008) ↓ (mRNA) (Le Vee et al., 2009) → (mRNA) (Le Vee et al., 2009) BCRP ↓ (mRNA) (Le Vee et al., 2008) ↓ (mRNA, protein) (Le Vee et al., 2009) ↓ (mRNA) (Le Vee et al., 2011) → (mRNA), ↑ (protein) (Le Vee et al., 2009) BSEP ↓ (mRNA) (Le Vee et al., 2008)
↓ (mRNA), ↑ (protein) (Diao et al., 2010)
↓ (mRNA) (Nguyen et al., 2015)→ (mRNA) (Le Vee et al., 2009)
↓ (mRNA), ↑ (protein) (Diao et al., 2010)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Le Vee et al., 2011) ↓ (mRNA) (Le Vee et al., 2009)
↓ (mRNA), → (protein) (Diao et al., 2010)P-gp → (mRNA) (Nguyen et al., 2015) ↓ (mRNA), → (protein) (Le Vee et al., 2009)
→ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Le Vee et al., 2011) → (mRNA, protein) (Le Vee et al., 2009) CYP1A2 ↓ (mRNA, protein) (Muntané-Relat et al., 1995)
↓ (mRNA) (Nguyen et al., 2015)↓ (protein) (Elkahwaji et al., 1999) ↓ (mRNA, protein) (Muntané-Relat et al., 1995)
↓ (mRNA) (Dickmann et al., 2011)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA, protein) (Muntané-Relat et al., 1995) CYP2A6 → (mRNA) (Kleine et al., 2008) CYP2B6 → (mRNA), ↓ (protein) (Aitken and Morgan, 2007)
→ (mRNA) (Nguyen et al., 2015)↓ (mRNA, protein) (Aitken and Morgan, 2007)
↓ (mRNA) (Dickmann et al., 2011)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA), ↓/→ (protein) (Aitken and Morgan, 2007) ↑ (mRNA), ↓ (protein)
(Aitken and Morgan, 2007)→ (mRNA), ↓ (protein)
(Aitken and Morgan, 2007)CYP2C8 ↓ (mRNA) (Aitken and Morgan, 2007)
↓ (mRNA) (Nguyen et al., 2015)↓ (protein as CYP2C) (Elkahwaji et al., 1999) ↓ (mRNA) (Kleine et al., 2008)
↓ (mRNA) (Aitken and Morgan, 2007)
↓ (mRNA) (Dickmann et al., 2011)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA) (Aitken and Morgan, 2007) ↓ (mRNA) (Aitken and Morgan, 2007) ↓ (mRNA) (Aitken and Morgan, 2007) CYP2C9 → (mRNA), ↓/→ (protein) (Aitken and Morgan, 2007)
→ (mRNA) (Nguyen et al., 2015)↓ (protein as CYP2C) (Elkahwaji et al., 1999) ↓ (mRNA, protein) (Aitken and Morgan, 2007)
↓ (mRNA) (Nguyen et al., 2015)→ (mRNA) (Aitken and Morgan, 2007) ↓ (mRNA), ↓/→ (protein) (Aitken and Morgan, 2007) → (mRNA), ↓ (protein) (Aitken and Morgan, 2007) CYP2C19 ↓ (mRNA) (Aitken and Morgan, 2007) ↓ (protein as CYP2C) (Elkahwaji et al., 1999) → (mRNA) (Aitken and Morgan, 2007)
↓ (mRNA) (Dickmann et al., 2011)
→ (mRNA) (Nguyen et al., 2015)→ (mRNA) (Aitken and Morgan, 2007) ↓ (mRNA) (Aitken and Morgan, 2007) → (mRNA) (Aitken and Morgan, 2007) CYP2D6 → (mRNA) (Nguyen et al., 2015) ↓ (mRNA) (Dickmann et al., 2011)
→ (mRNA) (Nguyen et al., 2015)CYP2E1 → (mRNA) (Nguyen et al., 2015) ↓ (protein) (Elkahwaji et al., 1999) → (mRNA) (Nguyen et al., 2015) CYP3A4 ↓ (mRNA, protein) (Muntané-Relat et al., 1995)
↓ (mRNA, protein) (Aitken and Morgan, 2007)
→ (mRNA) (Nguyen et al., 2015)↓ (protein) (Elkahwaji et al., 1999) ↓ (mRNA, protein) (Muntané-Relat et al., 1995)
↓ (mRNA) (Kleine et al., 2008)
↓ (mRNA, protein) (Aitken and Morgan, 2007)
↓ (mRNA) (Dickmann et al., 2011)
↓ (mRNA) (Nguyen et al., 2015)↓ (mRNA, protein) (Aitken and Morgan, 2007) ↓ (mRNA, protein) (Aitken and Morgan, 2007) ↓ (mRNA, protein) (Muntané-Relat et al., 1995)
↓ (mRNA, protein) (Aitken and Morgan, 2007)UGT1A1 ↓ (mRNA) (Nguyen et al., 2015) ↓ (mRNA) (Nguyen et al., 2015) IFNγ, interferon-γ; P-gp, P-glycoprotein; TGFβ, transforming growth factor-β; TNFα, tumor necrosis factor-α.
In this issue
Jump to section
- Article
- Abstract
- Introduction
- Renal Pharmacokinetics in Patients with Kidney Disease
- Changes in Drug Disposition in Extrarenal Organs During Kidney Disease
- Mechanisms Underlying the Functional Changes in Hepatic Proteins During Kidney Disease
- Biomarkers for Hepatic Drug-Metabolizing Enzymes and Transporters
- Future Directions
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters
Related Articles
Cited By...
More in this TOC Section
Similar Articles
Advertisement