Effect of CKD and Dialysis Modality on Exposure to Drugs Cleared by Nonrenal Mechanisms

Thomson, Benjamin; Nolin, Thomas D.; Velenosi, Thomas J.; Feere, David A.; Knauer, Michael J.; Asher, Linda; House, Andrew A.; Urquhart, Bradley L.

doi:10.1053/j.ajkd.2014.09.015

Cited by 54 publications

(43 citation statements)

References 39 publications

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“…Fexofenadine, a pharmacologic probe of drug transporter activity (eg, P-gp and OATP), exhibited significant increases in area under the plasma concentration-time curve as mediated by a decrease in systemic clearance in patients with CKD compared with healthy controls. 86 These results were consistent with a previous study by the same group that evaluated fexofenadine in patients with end-stage renal disease (ESRD). 87 Animal models of CKD are purported to result in alterations in transporter expression and function.…”

Section: Renal Transporters In Kidney Diseasessupporting

confidence: 92%

Effect of Disease Pathologies on Transporter Expression and Function

Atilano-Roque

Roda

Fogueri

et al. 2016

The Journal of Clinical Pharma

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Transporters are important determinants of drug absorption, distribution, and excretion. The clinical relevance of drug transporters in drug disposition and toxicology depends on their localization in liver, kidney, and brain. There has been growing evidence regarding the importance of disease status on alterations in metabolizing enzymes and transporter proteins. This review focuses on uptake and efflux transporter proteins in liver, kidney, and brain and discusses mechanisms of altered transporter expression and function secondary to disease.

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Section: Renal Transporters In Kidney Diseasessupporting

confidence: 92%

Effect of Disease Pathologies on Transporter Expression and Function

Atilano-Roque

Roda

Fogueri

et al. 2016

The Journal of Clinical Pharma

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“…In addition, the finding of no difference in plasma 4β-hydroxycholesterol concentration before kidney transplantation between ESRD patients with the CYP3A5*1 allele and patients without the CYP3A5*1 allele may imply that ESRD patients, even those with the CYP3A5*1 allele, have mainly CYP3A4 activity and little CYP3A5 activity before transplantation. The involvement of CYP3A5 polymorphism in CYP3A activity would explain the controversy of CYP3A activity in ESRD patients compared with healthy controls in previous studies [7,26,27], none of which genotyped the CYP3A5 gene. Furthermore, this may partially explain the paradox in the FDA review highlighting that approximately half of new molecular entities metabolized by CYP3A are markedly altered in kidney disease whereas the other half are unchanged [30].…”

Section: Discussionmentioning

confidence: 95%

“…A recent review has shown 35-75% decreases in liver CYP3A activity and 45-91% decreases in liver CYP3A protein expression in experimental circumstances in rats or mice with renal failure [25]. Human studies of CYP3A activity using midazolam as a probe yielded controversial results, which reported a decrease [7] and no difference [26,27] in CYP3A activity in ESRD patients compared with healthy controls. This paradox may be caused by alternation of midazolam pharmacokinetics in patients with renal failure.…”

Section: Discussionmentioning

confidence: 99%

“…However, several studies in rats [1][2][3][4][5][6] and in patients [7] have shown that renal failure also decreases the metabolic clearance of drugs, particularly those metabolized by cytochrome P450 (CYP) and substrates of some drug transporters. The underlying causes of altered functional expression of CYPs and drug transporters observed in kidney disease remain unclear, but several studies indicate that uremic toxins may play a role via transcriptional or translational modifications of CYP and drug transporter enzymes [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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CYP3A5 Polymorphism affects the increase in CYP3A activity after living Kidney transplantation in patients with end stage renal disease

Suzuki

Fujioka

Sato

et al. 2015

Clinical Therapeutics

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“…Importantly, drug interactions such as those caused by enzyme inhibition with itraconazole and enzyme induction after rifampin treatment can result in a dramatic 400‐fold range in CYP3A activity in human beings . Furthermore, conditions including cirrhosis , chronic hepatitis C infection , critical illness , cancer and kidney disease are associated with reduced CYP3A activity. Given such wide differences in enzyme activity among individuals, there has long been interest in various methods to quantify in vivo CYP3A function.…”

mentioning

confidence: 99%

Relationships between Endogenous Plasma Biomarkers of Constitutive Cytochrome P450 3A Activity and Single‐Time‐Point Oral Midazolam Microdose Phenotype in Healthy Subjects

Woolsey

Beaton

Choi

et al. 2015

Basic Clin Pharma Tox

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Due to high basal interindividual variation in cytochrome P450 3A (CYP3A) activity and susceptibility to drug interactions, there has been interest in the application of efficient probe drug phenotyping strategies, as well as endogenous biomarkers for assessment of in vivo CYP3A activity. The biomarkers 4b-hydroxycholesterol (4bHC) and 6b-hydroxycortisol (6bHCL) are sensitive to CYP3A induction and inhibition. However, their utility for the assessment of constitutive CYP3A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4bHC and 6bHCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single-time-point oral midazolam (MDZ) phenotyping strategy. Plasma 4bHC and 6bHCL metabolic ratios (MRs) were analysed in 51 healthy adult participants. CYP3A activity was determined after administration of an oral MDZ microdose (100 lg). Simple linear and multiple linear regression analyses were performed to assess relationships between MDZ oral clearance, biomarkers and subject covariates. Among study subjects, basal MDZ oral clearance, 4bHC and 6bHCL MRs ranged 6.5-, 10-and 13-fold, respectively. Participant age and alcohol consumption were negatively associated with MDZ oral clearance (p = 0.03 and p = 0.045, respectively), while weight and female sex were associated with lower plasma 4bHC MR (p = 0.0003 and p = 0.032, respectively). Neither 4bHC nor 6bHCL MRs were associated with MDZ oral clearance. Plasma 4bHC and 6bHCL MRs do not relate to MDZ single-time-point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals.It is well recognized that cytochromes P450 3A4 (CYP3A4) and CYP3A5 are important human drug-metabolizing enzymes with high interindividual variability in hepatic and intestinal activities. This is due to environmental, genetic, developmental, disease and seasonal control, including significant susceptibility to drug interactions [1][2][3][4][5][6]. Indeed, active CYP3A5 is genetically determined [7] while reduced CYP3A activity is associated with CYP3A4*22 [8], and peroxisome proliferator-activating receptor alpha (PPARa rs4253728) [9] while increased CYP3A activity is linked with CYP oxidoreductase POR*28 [10] polymorphism. Importantly, drug interactions such as those caused by enzyme inhibition with itraconazole and enzyme induction after rifampin treatment can result in a dramatic 400-fold range in CYP3A activity in human beings [11]. Furthermore, conditions including cirrhosis [12], chronic hepatitis C infection [13], critical illness [14], cancer [15,16] and kidney disease [17][18][19] are associated with reduced CYP3A activity. Given such wide differences in enzyme activity among individuals, there has long been interest in various methods to quantify in vivo CYP3A function.The most widely used and accepted method to assess CYP3A activity is to examine midazolam (MDZ) pharmacokinetics [20,21]. CYP3A phenotyping with MDZ has several advantages including rapid and specific elimina...

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Effect of CKD and Dialysis Modality on Exposure to Drugs Cleared by Nonrenal Mechanisms

Cited by 54 publications

References 39 publications

Effect of Disease Pathologies on Transporter Expression and Function

Effect of Disease Pathologies on Transporter Expression and Function

CYP3A5 Polymorphism affects the increase in CYP3A activity after living Kidney transplantation in patients with end stage renal disease

Relationships between Endogenous Plasma Biomarkers of Constitutive Cytochrome P450 3A Activity and Single‐Time‐Point Oral Midazolam Microdose Phenotype in Healthy Subjects

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