Differential effect of chronic renal failure on the pharmacokinetics of lidocaine in patients receiving and not receiving hemodialysis

Martin, Sara De; Orlando, Rocco; Bertoli, M; Pegoraro, Paola; Palatini, Pietro

doi:10.1016/j.clpt.2006.08.020

Cited by 68 publications

(40 citation statements)

References 30 publications

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“…In renal impairment, it was considered possible for eltrombopag exposure to increase due to downregulation of metabolic enzyme activity, as has been shown in preclinical experiments and reported in clinical studies for other highly metabolized drugs. [10][11][12] Alternatively, displacement from plasma proteins may result in decreased plasma total eltrombopag concentrations, without a corresponding change in plasma unbound eltrombopag concentrations as has been shown with phenytoin. 13 The literature also suggests that renal impairment may alter the activity of drug transporters in the liver and intestine.…”

Section: Discussionmentioning

confidence: 97%

Effect of Hepatic or Renal Impairment on Eltrombopag Pharmacokinetics

Bauman¹,

Vincent²,

Peng³

et al. 2011

The Journal of Clinical Pharmacology

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Eltrombopag, an oral, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of thrombocytopenia, is highly protein bound and primarily eliminated via metabolism in the liver and gastrointestinal tract. Single-dose eltrombopag pharmacokinetics were evaluated in participants with hepatic or renal impairment given possible changes in systemic exposure due to reduced plasma protein binding or reduced metabolism. All participants received a single 50-mg dose of eltrombopag. The adverse event profile was similar across groups, with headache, nausea, and back pain most frequently reported. Compared with healthy participants, participants with mild, moderate, or severe hepatic impairment had mean increases in AUC(0-∞) of 41%, 93%, and 80%, and participants with mild, moderate, or severe renal impairment had mean decreases in AUC(0-∞) of 32%, 36%, and 60%. There was high pharmacokinetic variability and significant overlap in exposures between participants with hepatic or renal impairment and healthy participants. Results suggest that patients with renal impairment may initiate eltrombopag with the standard 50-mg once-daily starting regimen, whereas patients with moderate or severe hepatic impairment should consider a lower 25-mg once-daily regimen. Patients with hepatic or renal impairment should be closely monitored for platelet response and safety, and eltrombopag doses should be adjusted accordingly.

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Section: Discussionmentioning

confidence: 97%

Effect of Hepatic or Renal Impairment on Eltrombopag Pharmacokinetics

Bauman¹,

Vincent²,

Peng³

et al. 2011

The Journal of Clinical Pharmacology

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“…This confounds its use as a specific CYP3A probe for whole-cell and in vivo studies (Sun et al, 2004). Pharmacokinetic studies in patients with varying degrees of kidney function have also used a variety of nonselective probe substrates for P450 enzymes (Ahmed et al, 1991;De et al, 2006). Although these studies clearly highlight that drug metabolism is differentially affected as kidney function declines, it is impossible to draw mechanistic conclusions about which specific P450 isozymes are affected.…”

Section: Discussionmentioning

confidence: 99%

“…Few studies have evaluated pharmacokinetics and drug metabolism in varying degrees of kidney disease despite the fact that CKD is known to be a progressive disorder whereby kidney function declines over time. Clinical studies in patients with varying degrees of CKD have demonstrated altered lidocaine and nicardipine pharmacokinetics; however, these drugs are metabolized by multiple P450 enzymes and are influenced by other pharmacokinetic factors in kidney disease, such as changes in plasma protein binding (Ahmed et al, 1991;De et al, 2006). Consequently, there is a lack of data investigating the effects of CKD on specific drug-metabolizing enzymes in the majority of the patient population.…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of Hepatic CYP3A and CYP2C Mediated Metabolism in Rats with Moderate Chronic Kidney Disease

Velenosi¹,

Fu²,

Luo³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Expression and activity of drug-metabolizing enzymes are decreased in severe kidney disease; however, only a small percentage of patients with chronic kidney disease (CKD) are at the final stage of the disease. This study aimed to determine the changes in drug-metabolizing enzyme function and expression in rats with varying degrees of kidney disease. Sprague-Dawley rats were subjected to surgical procedures that allowed the generation of three distinct models of kidney function: normal kidney function, moderate kidney function, and severe kidney disease. Forty-two days after surgery, rats were sacrificed and hepatic CYP3A and CYP2C expression was determined. In addition, enzymatic activity was determined in liver microsomes by evaluating midazolam (CYP3A), testosterone (CYP3A and CYP2C), and tolbutamide (CYP2C) enzyme kinetics. Both moderate and severe kidney disease were associated with a reduction in CYP3A2 and CYP2C11 expression (p < 0.05). Likewise, moderate kidney disease resulted in more than a 60% decrease in enzyme activity (V max ) for CYP2C11 and CYP3A, compared with controls (p < 0.05). When the degree of kidney disease was correlated with metabolic activity, an exponential decline in CYP2C-and CYP3A-mediated metabolism was observed. Our results demonstrate that CYP3A and CYP2C expression and activity are decreased in both moderate and severe CKD. Our data suggest that drug metabolism is significantly decreased in the earlier stages of CKD and imply that patients with moderate CKD may be subject to unpredictable pharmacokinetics.

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“…Mean values of CL int, liver for LID N-deethylation calculated from kinetic parameters generated in the absence and presence of BSA were 28 and 75 l/h, respectively, whereas predicted values of CL H were 9.1 and 21 l/h, respectively. CL int, in vivo and in vivo CL H were calculated from data reported for healthy volunteers administered intravenous LID (1-1.5 mg/kg) in four recent kinetic studies (Orlando et al, 2003(Orlando et al, , 2004Olkkola et al, 2005;De Martin et al, 2006). Mean values of CL int, in vivo and in vivo CL H from the four studies ranged from 142 to 198 and from 32 to 40 l/h, respectively.…”

Section: Downloaded Frommentioning

confidence: 99%

Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

Wattanachai¹,

Tassaneeyakul²,

Rowland³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Long-chain unsaturated fatty acids inhibit several cytochrome P450 and UDP-glucuronosyltransferase (UGT) enzymes involved in drug metabolism, including CYP2C8, CYP2C9, UGT1A9, UGT2B4, and UGT2B7. Bovine serum albumin (BSA) enhances these cytochrome P450 and UGT activities by sequestering fatty acids that are released from membranes, especially with human liver microsomes (HLM) as the enzyme source. Here, we report the effects of BSA on CYP1A2-catalyzed phenacetin (

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Differential effect of chronic renal failure on the pharmacokinetics of lidocaine in patients receiving and not receiving hemodialysis

Cited by 68 publications

References 30 publications

Effect of Hepatic or Renal Impairment on Eltrombopag Pharmacokinetics

Effect of Hepatic or Renal Impairment on Eltrombopag Pharmacokinetics

Down-Regulation of Hepatic CYP3A and CYP2C Mediated Metabolism in Rats with Moderate Chronic Kidney Disease

Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

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