In Vivo Alterations in Drug Metabolism and Transport Pathways in Patients with Chronic Kidney Diseases

Joy, Melanie S.; Frye, Reginald F.; Nolin, Thomas D.; Roberts, Brittney V.; La, Mary; Wang, Jinzhao; Brouwer, Kim L. R.; Dooley, Mary Anne; Falk, Ronald J.

doi:10.1002/phar.1347

Cited by 26 publications

(19 citation statements)

References 41 publications

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“…Although these data are illustrative, the effect on expression and activity of some cytochrome P450 isoenzymes is controversial. For example, some studies have identified progressive reductions in clearance by CYP2D6 (46), whereas others have found no difference in enzyme activity in advanced CKD for CYP3A4/5 (16,46) and CYP2C9 (47). Instead, the changes in metabolic clearances noted in CKD may also relate to changes in expression or function of drug transporters (for example, those on the hepatocyte cell membrane).…”

Section: Volume Of Distribution (Vd)mentioning

confidence: 99%

Clinical Pharmacokinetics in Kidney Disease

Lea‐Henry

Carland

Stocker

et al. 2018

CJASN

163

139

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Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Prescribing to patients with kidney disease requires knowledge about the drug, the extent of the patient's altered physiology, and pharmacokinetic principles that influence the design of dosing regimens. There are multiple physiologic effects of impaired kidney function, and the extent to which they occur in an individual at any given time can be difficult to define. Although some guidelines are available for dosing in kidney disease, they may be on the basis of limited data or not widely applicable, and therefore, an understanding of pharmacokinetic principles and how to apply them is important to the practicing clinician. Whether kidney disease is acute or chronic, drug clearance decreases, and the volume of distribution may remain the same or increase. Although in CKD, these changes progress relatively slowly, they are dynamic in AKI, and recovery is possible depending on the etiology and treatments. This, and the use of kidney replacement therapies further complicate attempts to quantify drug clearance at the time of prescribing and dosing in AKI. The required change in the dosing regimen can be estimated or even quantitated in certain instances through the application of pharmacokinetic principles to guide rational drug dosing. This offers an opportunity to provide personalized medical care and minimizes adverse drug events from either under- or overdosing. We discuss the principles of pharmacokinetics that are fundamental for the design of an appropriate dosing regimen in this review.

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Section: Volume Of Distribution (Vd)mentioning

confidence: 99%

Clinical Pharmacokinetics in Kidney Disease

Lea‐Henry

Carland

Stocker

et al. 2018

CJASN

163

139

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“…In patients with GN, proteinuria, and hypoalbuminemia but creatinine clearance (CrCL) .90 ml/min, apparent clearance of fexofenadine (substrate of P-glycoprotein and other transporters) is decreased 40% compared with healthy controls with a comparable GFR (16). Further, the elimination t 1/2 of fexofenadine is prolonged in patients with GN compared with patients with ESKD and healthy controls, suggesting an increased Vd with GN (16). Yet, flurbiprofen (CYP2C9 substrate) had similar pharmacokinetics in patients with GN and CrCL.90 ml/min as in patients with ESKD.…”

Section: Ckdmentioning

confidence: 99%

Clinical Pharmacokinetics in Kidney Disease

Roberts

Sevastos

Carland

et al. 2018

CJASN

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A change in pharmacokinetics can alter drug exposure and predispose the patient to either over-or underdosing, potentially resulting in adverse drug reactions or therapeutic failure. Kidney disease is characterized by multiple physiologic effects, which induce clinically significant changes in pharmacokinetics. These vary between individuals and may be quantitated in certain instances. An understanding of pharmacokinetic concepts is, therefore, important for a rational approach to the design of drug dosing regimens for the delivery of personalized medical care. Whether kidney disease is acute or chronic, drug clearance decreases and the volume of distribution may remain unchanged or increase. AKI is defined by dynamic changes in kidney function, which complicates attempts to accurately quantify drug clearance. In contrast, changes in drug clearance progress more slowly with CKD. In general, kidney replacement therapies increase drug clearance, but the extent to which this occurs depends on the modality used and its duration, the drug's properties, and the timing of drug administration. However, the changes in drug handling associated with kidney disease are not isolated to reduced kidney clearance and an appreciation of the scale of potential derangements is important. In most instances, the first dose administered in patients with kidney disease is the same as in patients with normal kidney function. However, in some cases, a higher (loading) initial dose is given to rapidly achieve therapeutic concentrations, followed by a lower maintenance dose, as is well described when prescribing anti-infectives to patients with sepsis and AKI. This review provides an overview of how pharmacokinetic principles can be applied to patients with kidney disease to personalize dosage regimens. Patients with kidney disease are a vulnerable population and the increasing prevalence of kidney disease means that these considerations are important for all prescribers.

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“…Microbiota-derived uremic toxins interact with several nonrenal clearance pathways, thereby potentially modifying drug dosing-exposure-response relationships in patients with kidney disease [14–17]. In fact, alterations in the functional expression of drug metabolizing enzymes and transporters in kidney disease are well documented [18–21], and several microbial toxins are potential mediators [22,23].…”

Section: Introductionmentioning

confidence: 99%

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

Prokopienko

Nolin

2017

Expert Review of Clinical Pharmacology

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Introduction Scientific interest in the gut microbiota is increasing due to improved understanding of its implications in human health and disease. In patients with kidney disease, gut microbiota-derived uremic toxins directly contribute to altered nonrenal drug clearance. Microbial imbalances, known as dysbiosis, potentially increase formation of microbiota-derived toxins, and diminished renal clearance leads to toxin accumulation. High concentrations of microbiota-derived toxins such as indoxyl sulfate and p-cresol sulfate perpetrate interactions with drug metabolizing enzymes and transporters, which provides a mechanistic link between increases in drug-related adverse events and dysbiosis in kidney disease. Areas Covered This review summarizes the effects of microbiota-derived uremic toxins on hepatic phase I and phase II drug metabolizing enzymes and drug transporters. Research articles that tested individual toxins were included. Therapeutic strategies to target microbial toxins are also discussed. Expert Commentary Large interindividual variability in toxin concentrations may explain some differences in nonrenal clearance of medications. Advances in human microbiome research provide unique opportunities to systematically evaluate the impact of individual and combined microbial toxins on drug metabolism and transport, and to explore microbiota-derived uremic toxins as potential therapeutic targets.

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In Vivo Alterations in Drug Metabolism and Transport Pathways in Patients with Chronic Kidney Diseases

Cited by 26 publications

References 41 publications

Clinical Pharmacokinetics in Kidney Disease

Clinical Pharmacokinetics in Kidney Disease

Clinical Pharmacokinetics in Kidney Disease

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

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