Pharmacokinetic effects of altered plasma protein binding of drugs in renal disease

Keller, Frieder; Maïga, Mahamane Kalil; Neumayer, Hans‐H.; Lode, H.; Distler, A.

doi:10.1007/bf03189651

Cited by 63 publications

(42 citation statements)

References 58 publications

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“…This limitation to our study is important in light of the potential effect of the hypoalbuminemia observed in our patients. Hypoalbuminemia may cause a reduced plasma protein binding of drugs, resulting in a potential increase in drug concentration at the site of action [36,37]. This reduced protein binding may also give rise to accelerated overall clearance of the drug.…”

Section: Discussionmentioning

confidence: 97%

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Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease

2009

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Obesity is associated with an increased concentration of inflammatory mediators, which in turn, in adults, reduces the response to calcium channel blockers (CCBs). We reviewed the medical charts of 263 pediatric nephrology patients with renal conditions, with the aim of studying the effect of obesity on the response to L-type CCBs, angiotensin interrupting agents (ANGIs), or a combination of the two. Forty-eight patients were ultimately enrolled in the study: 25 obese and 23 non-obese patients. The effect of the treatments on lowering the blood pressure was compared in obese versus non-obese patients. The systolic response to CCBs, measured as at least a 10% reduction from the baseline, was significantly lower in the obese (12.5%) patients than in the non-obese (52.9%) ones. The differences in diastolic response (58.8 and 25% for non-obese and obese patients, respectively) did not reach significance. The percentage response to CCBs, however, was significantly less in the obese patients than in the non-obese patients for both systolic and diastolic blood pressure. Corticosteroids also significantly influenced the response to CCBs in terms of diastolic pressure (62.9 and 25% for non-obese and obese patients, respectively). None of the tested covariates, including obesity, was found to significantly influence the response to ANGIs alone or in various combinations with CCBs. In conclusion, obesity and corticosteroid therapy should be considered when initiating antihypertensive drug treatment in children with kidney disease as both may contribute to a reduced efficacy of the antihypertensive therapy.

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Section: Discussionmentioning

confidence: 97%

“…This reduced protein binding may also give rise to accelerated overall clearance of the drug. These two potential mechanisms often offset each other and render the influence of hypoalbuminemia on the pharmacokinetics negligible [36][37][38].…”

Section: Discussionmentioning

confidence: 97%

Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease

2009

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“…Impaired renal function was reported to affect the extent of plasma protein binding, which might affect the distribution and elimination of drugs (13,15). However, according to the U.S. Food and Drug Administration guidance (16), plasma protein binding of drugs with a relatively low extent of plasma protein binding (e.g., F u Ͼ 20%) is not markedly affected by impaired renal function.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, several studies have demonstrated that changes in renal transporters may affect renal clearance (6,8). Additionally, abnormal plasma protein binding was reported to affect drug disposition in patients with renal impairment (13).…”

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confidence: 99%

Effects of Renal Impairment on the Pharmacokinetics of Morinidazole: Uptake Transporter-Mediated Renal Clearance of the Conjugated Metabolites

Zhong

Xie

et al. 2014

Antimicrob Agents Chemother

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Morinidazole is a novel 5-nitroimidazole antimicrobial drug that undergoes extensive metabolism in humans via N ؉ -glucuronidation (N ؉ -glucuronide of S-morinidazole [M8-1] and N ؉ -glucuronide of R-morinidazole [M8-2]) and sulfation (sulfate conjugate of morinidazole [M7]). Our objectives were to assess the effects of renal impairment on the pharmacokinetics (PK) of morinidazole and to elucidate the potential mechanisms. In this parallel-group study, healthy subjects and patients with severe renal impairment received an intravenous infusion of 500 mg of morinidazole. Plasma and urine samples were collected and analyzed. The areas under the plasma concentration-time curves (AUC) for M7, M8-1, and M8-2 were 15.1, 20.4, and 17.4 times higher, respectively, in patients with severe renal impairment than in healthy subjects, while the AUC for morinidazole was 1.5 times higher. The urinary recovery of the major metabolites was not significantly different between the two groups over 0 to 48 h, but the renal clearances of M7, M8-1, and M8-2 in patients were 85.3%, 92.5%, and 92.2% lower, respectively. In vitro transporter studies revealed that M7 is a substrate for organic anion transporter 1 (OAT1) and OAT3 (K m ‫؍‬ 28.6 and 54.0 M, respectively). Only OAT3 transported M8-1 and M8-2. Morinidazole was not a substrate for the transporter-transfected cells examined. These results revealed that the function or activity of renal uptake transporters might be impaired in patients with severe renal impairment, which accounted for dramatically increased plasma exposure and reduced renal clearance of the conjugated metabolites of morinidazole, the substrates of renal transporters in patients. It will help clinicians to adjust the dose in patients with severe renal impairment and to predict possible transporter-based drug-drug interactions.is a novel 5-nitroimidazole antimicrobial agent indicated for the treatment of infections caused by amoeba, Trichomonas vaginalis, and anaerobic bacteria. 5-Nitroimidazole antimicrobial drugs act via nitroreduction of the molecules in the pathogens (1). As an analog of metronidazole, morinidazole appears to show greater antiparasitic potency against T. vaginalis and amoebic protozoa, but it exhibited relatively weaker toxicity in vitro and in preclinical animal studies compared with metronidazole (2).Following intravenous administration, morinidazole was reported to undergo extensive metabolism in healthy humans, principally via N ϩ -glucuronidation (yielding the N ϩ -glucuronide of S-morinidazole [M8-1] and N ϩ -glucuronide of R-morinidazole [M8-2]) and O-sulfation (yielding the sulfate conjugate of morinidazole [M7]) ( Fig. 1) (3). Renal elimination of morinidazole and its main metabolites accounted for about 71% of a 500-mg dose over 0 to 36 h (3). The primary components in urine were M8-2 (28.4% of the dose), followed by morinidazole (21.2%), M8-1 (6.6%), and M7 (13.0%) (unpublished data). Because of the significant role of the kidney in elimination of morinidazole and its metabolites, it ...

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“…Since tacrolimus largely binds to erythrocytes, anemia of CKD may cause the alteration in tacrolimus pharmacokinetics [15]. Edematous status caused by proteinuria also alters the Vd of the drug [16,17].…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Oral Tacrolimus in Patients with Glomerulonephritis

Shim¹,

Kim²,

Choi³

et al. 2016

Int J Clin Pharmacol Pharmacother

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Objective: Tacrolimus as an immunosuppressant is used to treat for several types of glomerulonephritis. Narrow therapeutic window and huge interindividual variability of tacrolimus make it impossible to predict its serum level. Hence, the purpose of this study was to derive population pharmacokinetic model for tacrolimus in glomerulonephritis patients. Materials and methods: Adult patients diagnosed with glomerulonephritis and treated with oral tacrolimus were included. Electronic medical records were reviewed retrospectively to access clinical findings and demographic data. Population pharmacokinetics of tacrolimus was evaluated using nonlinear mixed effect model by first-order conditional estimation with interaction algorithm. Results: One hundred and forty-five patients were included in this study and one thousand and nine hundreds thirty-eight blood samples were analyzed. The estimated apparent clearance (CL/F) was 19.5 L/h, and apparent volume of distribution (V/F) was 380 L. The final model suggested that serum creatinine levels were negatively correlated with both CL/F and V/F whereas serum albumin levels were positively associated with V/F. Conclusion: Various factors affecting tacrolimus pharmacokinetics were explored. The findings of this study pointed out that tacrolimus pharmacokinetics were related to patients' kidney function and serum albumin level in glomerulonephritis patients. Developed model may guide individualized tacrolimus therapy in glomerulonephritis patients and improve therapeutic outcomes in glomerulonephritis patients.

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Pharmacokinetic effects of altered plasma protein binding of drugs in renal disease

Cited by 63 publications

References 58 publications

Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease

Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease

Effects of Renal Impairment on the Pharmacokinetics of Morinidazole: Uptake Transporter-Mediated Renal Clearance of the Conjugated Metabolites

Population Pharmacokinetic Analysis of Oral Tacrolimus in Patients with Glomerulonephritis

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