N-acetylcysteine in Kidney Disease: Molecular Mechanisms, Pharmacokinetics, and Clinical Effectiveness
2024; Elsevier BV; Volume: 9; Issue: 10 Linguagem: Inglês
10.1016/j.ekir.2024.07.020
ISSN2468-0249
AutoresEstefani Yaquelin Hernández‐Cruz, Omar Emiliano Aparicio‐Trejo, Fadi A. Hammami, Daniel Bar‐Shalom, Martin Tepel, José Pedraza-Chaverri, Alexandra Scholze,
Tópico(s)Acute Kidney Injury Research
ResumoN-acetylcysteine (NAC) has shown beneficial effects in both acute kidney disease and chronic kidney disease (CKD) in preclinical and clinical studies. Different dosage and administration forms of NAC have specific pharmacokinetic properties that determine the temporal pattern of plasma concentrations of NAC and its active metabolites. Especially in acute situations with short-term NAC administration, appropriate NAC and glutathione (GSH) plasma concentrations should be timely ensured. For oral dosage forms, bioavailability needs to be established for the respective NAC formulation. Kidney function influences NAC pharmacokinetics, including a reduction of NAC clearance in advanced CKD. In addition, mechanisms of action underlying beneficial NAC effects depend on kidney function as well as comorbidities, both involving GSH deficiency, alterations in nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent signaling, oxidative stress, mitochondrial dysfunction, and disturbed mitochondrial bioenergetics. This also applies to nonrenal NAC mechanisms. The timing of preventive NAC administration in relation to potential injury is important. NAC administration seems most effective either preceding, or preceding and paralleling conditions that induce tissue damage. Furthermore, studies suggest that very high concentrations of NAC should be avoided because they could exert reductive stress. Delayed administration of NAC might interfere with endogenous repair mechanisms. In conclusion, studies on NAC treatment regimens need to account for both NAC pharmacokinetics and NAC molecular effects. Kidney function of the patient population and pathomechanisms of the kidney disease should guide rational NAC trial design. A targeted trial approach and biomarker-guided protocols could pave the way for the use of NAC in precision medicine. N-acetylcysteine (NAC) has shown beneficial effects in both acute kidney disease and chronic kidney disease (CKD) in preclinical and clinical studies. Different dosage and administration forms of NAC have specific pharmacokinetic properties that determine the temporal pattern of plasma concentrations of NAC and its active metabolites. Especially in acute situations with short-term NAC administration, appropriate NAC and glutathione (GSH) plasma concentrations should be timely ensured. For oral dosage forms, bioavailability needs to be established for the respective NAC formulation. Kidney function influences NAC pharmacokinetics, including a reduction of NAC clearance in advanced CKD. In addition, mechanisms of action underlying beneficial NAC effects depend on kidney function as well as comorbidities, both involving GSH deficiency, alterations in nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent signaling, oxidative stress, mitochondrial dysfunction, and disturbed mitochondrial bioenergetics. This also applies to nonrenal NAC mechanisms. The timing of preventive NAC administration in relation to potential injury is important. NAC administration seems most effective either preceding, or preceding and paralleling conditions that induce tissue damage. Furthermore, studies suggest that very high concentrations of NAC should be avoided because they could exert reductive stress. Delayed administration of NAC might interfere with endogenous repair mechanisms. In conclusion, studies on NAC treatment regimens need to account for both NAC pharmacokinetics and NAC molecular effects. Kidney function of the patient population and pathomechanisms of the kidney disease should guide rational NAC trial design. A targeted trial approach and biomarker-guided protocols could pave the way for the use of NAC in precision medicine. NAC has been investigated for reducing kidney damage and CKD-related morbidity. This comprehensive review focuses on NAC effects and mechanisms of action, timing of NAC administration, and pharmacokinetics of NAC and its metabolites with relevance for kidney disease. We provide a narrative review without strict inclusion and exclusion criteria. The literature search strategy is outlined in the Supplementary methods. The acetyl group is cleaved from NAC, resulting in free cysteine. NAC-deacetylating acylase shows the highest activity in the kidney, followed by the liver.1Yamauchi A. Ueda N. Hanafusa S. Yamashita E. Kihara M. Naito S. Tissue distribution of and species differences in deacetylation of N-acetyl-L-cysteine and immunohistochemical localization of acylase I in the primate kidney.J Pharm Pharmacol. 2002; 54: 205-212https://doi.org/10.1211/0022357021778394Crossref PubMed Scopus (32) Google Scholar After oral administration, deacetylation mainly takes place in the intestinal mucosa.2Sjödin K. Nilsson E. Hallberg A. Tunek A. Metabolism of N-acetyl-L-cysteine. Some structural requirements for the deacetylation and consequences for the oral bioavailability.Biochem Pharmacol. 1989; 38: 3981-3985https://doi.org/10.1016/0006-2952(89)90677-1Crossref PubMed Scopus (110) Google Scholar The liver takes up cysteine via the portal vein, and more than half of the resorbed cysteine and other sulfur-containing amino acids are used by the liver to synthesize GSH, which is exported to the plasma.3Garcia R.A. Stipanuk M.H. The splanchnic organs, liver and kidney have unique roles in the metabolism of sulfur amino acids and their metabolites in rats.J Nutr. 1992; 122: 1693-1701https://doi.org/10.1093/jn/122.8.1693Abstract Full Text PDF PubMed Scopus (82) Google Scholar Liver GSH efflux can be substantially increased by vasopressin or angiotensin II, contributing to GSH delivery during stress conditions.4Sies H. Brigelius R. Graf P. Hormones, glutathione status and protein S-thiolation.Adv Enzyme Regul. 1987; 26: 175-189https://doi.org/10.1016/0065-2571(87)90013-6Crossref PubMed Scopus (46) Google Scholar GSH is an important cellular reductant, and redox-signaling is closely related to the ratio of GSH to glutathione disulfide (GSSG) and mitochondrial GSH content. The kidneys take up half of the plasma GSH originating from the liver.3Garcia R.A. Stipanuk M.H. The splanchnic organs, liver and kidney have unique roles in the metabolism of sulfur amino acids and their metabolites in rats.J Nutr. 1992; 122: 1693-1701https://doi.org/10.1093/jn/122.8.1693Abstract Full Text PDF PubMed Scopus (82) Google Scholar Normal kidney function is highly dependent on GSH supply due to the high rate of aerobic metabolism in tubule cells.5Lash L.H. Role of glutathione transport processes in kidney function.Toxicol Appl Pharmacol. 2005; 204: 329-342https://doi.org/10.1016/j.taap.2004.10.004Crossref PubMed Scopus (144) Google Scholar Proximal tubule cells obtain GSH from the plasma by transport via the basolateral membrane and by synthesis from cysteine.5Lash L.H. Role of glutathione transport processes in kidney function.Toxicol Appl Pharmacol. 2005; 204: 329-342https://doi.org/10.1016/j.taap.2004.10.004Crossref PubMed Scopus (144) Google Scholar It has been stressed that NAC's effectiveness as a GSH precursor depends on GSH depletion and the functionality of GSH synthesis pathways.6Rushworth G.F. Megson I.L. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits.Pharmacol Ther. 2014; 141: 150-159https://doi.org/10.1016/j.pharmthera.2013.09.006Crossref PubMed Scopus (520) Google Scholar Both impaired GSH synthesis and GSH depletion are observed in kidney disease. In advanced CKD, mononuclear cell and plasma GSH were significantly reduced compared to healthy controls and earlier CKD stages.7Tomás-Simó P. D'Marco L. Romero-Parra M. et al.Oxidative stress in non-dialysis-dependent chronic kidney disease patients.Int J Environ Res Public Health. 2021; 18: 7806https://doi.org/10.3390/ijerph18157806Crossref PubMed Scopus (10) Google Scholar,8Vida C. Oliva C. Yuste C. et al.Oxidative stress in patients with advanced CKD and renal replacement therapy: the key role of peripheral blood leukocytes.Antioxidants (Basel). 2021; 10: 1155https://doi.org/10.3390/antiox10071155Crossref PubMed Scopus (13) Google Scholar By contrast, in early CKD (CKD G1–3a), circulating GSH was not reduced.9Ceballos-Picot I. Witko-Sarsat V. Merad-Boudia M. et al.Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure.Free Radic Biol Med. 1996; 21: 845-853https://doi.org/10.1016/0891-5849(96)00233-xCrossref PubMed Scopus (0) Google Scholar The Nrf2 regulates essential enzymes of GSH metabolism. The state of the Nrf2 system depends on CKD stage and comorbidities.10Aranda-Rivera A.K. Cruz-Gregorio A. Pedraza-Chaverri J. Scholze A. Nrf2 activation in chronic kidney disease: promises and pitfalls.Antioxidants (Basel). 2022; 11: 1112https://doi.org/10.3390/antiox11061112Crossref PubMed Scopus (26) Google Scholar Gene expression of the rate-controlling enzyme for GSH synthesis (glutamate-cysteine ligase), and of glycine and cysteine or glutamate transporters (SLC6A9, SLC7A11), is positively regulated by Nrf2.11Hayes J.D. Dinkova-Kostova A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism.Trends Biochem Sci. 2014; 39: 199-218https://doi.org/10.1016/j.tibs.2014.02.002Abstract Full Text Full Text PDF PubMed Scopus (1571) Google Scholar Furthermore, gamma-glutamyltransferase is a positively regulated Nrf2 target. It mediates cysteine availability for GSH synthesis. The renal proximal tubular epithelium shows the highest gamma-glutamyltransferase activity. The expression of both Nrf2 and Nrf2 targets is altered in CKD and acute kidney injury (AKI).12Nezu M. Souma T. Yu L. et al.Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression.Kidney Int. 2017; 91: 387-401https://doi.org/10.1016/j.kint.2016.08.023Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 13Rubio-Navarro A. Vázquez-Carballo C. Guerrero-Hue M. et al.Nrf2 plays a protective role against intravascular hemolysis-mediated acute kidney injury.Front Pharmacol. 2019; 10: 740https://doi.org/10.3389/fphar.2019.00740Crossref PubMed Scopus (35) Google Scholar, 14Juul-Nielsen C. Shen J. Stenvinkel P. Scholze A. Systematic review of the nuclear factor erythroid 2-related factor 2 (NRF2) system in human chronic kidney disease: alterations, interventions and relation to morbidity.Nephrol Dial Transplant. 2022; 37: 904-916https://doi.org/10.1093/ndt/gfab031Crossref PubMed Scopus (16) Google Scholar In corroboration of the GSH data above, an endogenous activation of the Nrf2 system is found in earlier stages of CKD, whereas a suppression is seen in advanced CKD.15Leal V.O. Saldanha J.F. Stockler-Pinto M.B. et al.NRF2 and NF-κB mRNA expression in chronic kidney disease: a focus on nondialysis patients.Int Urol Nephrol. 2015; 47: 1985-1991https://doi.org/10.1007/s11255-015-1135-5Crossref PubMed Scopus (18) Google Scholar, 16Shen J. Rasmussen M. Dong Q.R. Tepel M. Scholze A. Expression of the NRF2 target gene NQO1 is enhanced in mononuclear cells in human chronic kidney disease.Oxid Med Cell Longev. 2017; 20179091879https://doi.org/10.1155/2017/9091879Crossref Scopus (24) Google Scholar, 17Rasmussen M. Hansen K.H. Scholze A. Nrf2 protein serum concentration in human CKD shows a biphasic behavior.Antioxidants (Basel). 2023; 12: 932https://doi.org/10.3390/antiox12040932Crossref PubMed Scopus (5) Google Scholar As a result, NAC effects are expected to differ between patient populations. Methylglyoxal is an important uremic toxin. NAC, like metformin and GSH, acts as a methylglyoxal scavenger. They inhibit methylglyoxal-induced protein glycation by serving as alternative targets for glycation processes.18Zeng J. Davies M.J. Protein and low molecular mass thiols as targets and inhibitors of glycation reactions.Chem Res Toxicol. 2006; 19: 1668-1676https://doi.org/10.1021/tx0602158Crossref PubMed Scopus (52) Google Scholar,19Bollong M.J. Lee G. Coukos J.S. et al.A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling.Nature. 2018; 562: 600-604https://doi.org/10.1038/s41586-018-0622-0Crossref PubMed Scopus (205) Google Scholar In addition, administration of NAC resulted in a substantial increase of native, reduced transthyretin. Changes in posttranslational protein modifications of transthyretin were reversible and a function of the NAC plasma concentration, with S-cysteinylated transthyretin declining significantly from 30 μmol/l NAC.20Henze A. Raila J. Scholze A. Zidek W. Tepel M. Schweigert F.J. Does N-acetylcysteine modulate post-translational modifications of transthyretin in hemodialysis patients?.Antioxid Redox Signal. 2013; 19: 1166-1172https://doi.org/10.1089/ars.2012.5125Crossref PubMed Scopus (8) Google Scholar NAC has shown antihypertensive effects when added to angiotensin-converting-enzyme inhibitor therapy in smokers (600 mg p.o., 3 times daily for 3 weeks)21Barrios V. Calderón A. Navarro-Cid J. Lahera V. Ruilope L.M. N-acetylcysteine potentiates the antihypertensive effect of ACE inhibitors in hypertensive patients.Blood Press. 2002; 11: 235-239https://doi.org/10.1080/08037050213760Crossref PubMed Scopus (32) Google Scholar and was suggested to inhibit angiotensin-converting-enzyme activity in healthy volunteers (∼2.5 g i.v. over 2 hours).22Boesgaard S. Aldershvile J. Poulsen H.E. Christensen S. Dige-Petersen H. Giese J. N-acetylcysteine inhibits angiotensin converting enzyme in vivo.J Pharmacol Exp Ther. 1993; 265: 1239-1244PubMed Google Scholar In patients with diabetes, vasoconstriction elicited by physiologic doses of aldosterone was reduced by NAC (∼4 g i.v. over 1 hour).23Finsen S.H. Hansen M.R. Hansen P.B.L. Mortensen S.P. Aldosterone induces vasoconstriction in individuals with type 2 diabetes: effect of acute antioxidant administration.J Clin Endocrinol Metab. 2021; 106: e1262-e1270https://doi.org/10.1210/clinem/dgaa867Crossref PubMed Scopus (4) Google Scholar In healthy subjects and in CKD G3, i.v. NAC increased renal blood flow (∼7 g i.v. over 2 hours).24Sandilands E.A. Rees J.M.B. Raja K. et al.Acetylcysteine has No Mechanistic Effect in Patients at Risk of Contrast-Induced Nephropathy: A Failure of Academic Clinical Science.Clin Pharmacol Ther. 2022; 111: 1222-1238https://doi.org/10.1002/cpt.2541Crossref PubMed Scopus (4) Google Scholar Although excessive oxidants cause cellular damage, a physiological oxidant level is required for proper redox signaling. Upon excessive load of reductants, reductive stress can occur.25Sies H. Oxidative eustress: the physiological role of oxidants.Sci China (Life Sci). 2023; 66: 1947-1948https://doi.org/10.1007/s11427-023-2336-1Crossref PubMed Scopus (4) Google Scholar NAC (EC50 4000 μmol/l) was able to elicit GSH-dependent reductive stress and cytotoxicity.26Zhang H. Limphong P. Pieper J. et al.Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.FASEB J. 2012; 26: 1442-1451https://doi.org/10.1096/fj.11-199869Crossref PubMed Scopus (155) Google Scholar In addition, NAC administration to tumor xenografts increased tumor angiogenesis by reducing reactive oxygen species signaling (1 g/l NAC in drinking water for 7 weeks).27Wang T. Dong Y. Huang Z. et al.Antioxidants stimulate BACH1-dependent tumor angiogenesis.J Clin Invest. 2023; 133e169671https://doi.org/10.1172/JCI169671Crossref Scopus (1) Google Scholar In a mouse model of AKI-to-CKD progression, the administration of NAC before and for 21 days after AKI increased cellular dysfunction and the progression to CKD through an impairment of the endogenous, Nrf2-mediated antioxidant responses.28Small D.M. Sanchez W.Y. Roy S.F. et al.N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenous antioxidant responses.Am J Physiol Ren Physiol. 2018; 314: F956-F968https://doi.org/10.1152/ajprenal.00057.2017Crossref PubMed Scopus (11) Google Scholar NAC is marketed in solution for i.v., oral, and respiratory administration or as tablets, effervescent tablets, capsules, granules, and powder for oral administration. In plasma, NAC is found reduced and oxidized, including protein bound.29Olsson B. Johansson M. Gabrielsson J. Bolme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine.Eur J Clin Pharmacol. 1988; 34: 77-82https://doi.org/10.1007/BF01061422Crossref PubMed Scopus (277) Google Scholar In healthy subjects, the first-pass metabolism of NAC is high and mainly represents NAC deacetylation in the intestinal mucosa.2Sjödin K. Nilsson E. Hallberg A. Tunek A. Metabolism of N-acetyl-L-cysteine. Some structural requirements for the deacetylation and consequences for the oral bioavailability.Biochem Pharmacol. 1989; 38: 3981-3985https://doi.org/10.1016/0006-2952(89)90677-1Crossref PubMed Scopus (110) Google Scholar Oral bioavailability is about 10% for total NAC (8.3% with 600 mg and 11.6% with 1200 mg effervescent tablet, Mucomyst, Tika30Borgström L. Kågedal B. Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man.Biopharm Drug Dispos. 1990; 11: 131-136https://doi.org/10.1002/bdd.2510110205Crossref PubMed Scopus (55) Google Scholar; 9.1% with 400 mg effervescent tablet, ACO Läkemedel29Olsson B. Johansson M. Gabrielsson J. Bolme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine.Eur J Clin Pharmacol. 1988; 34: 77-82https://doi.org/10.1007/BF01061422Crossref PubMed Scopus (277) Google Scholar). Maximal plasma concentrations (Cmax) for total NAC after a single dose were approximately 14 μmol/l with 600 mg (effervescent tablet, Mucomyst, Tika, time to reach Cmax at ∼40 minutes),30Borgström L. Kågedal B. Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man.Biopharm Drug Dispos. 1990; 11: 131-136https://doi.org/10.1002/bdd.2510110205Crossref PubMed Scopus (55) Google Scholar approximately 17 μmol/l with 600 mg (uncoated tablets, Fluimucil, Zambon, time to reach Cmax at ∼70 minutes),31Papi A. Di Stefano A.F.D. Radicioni M. Pharmacokinetics and safety of single and multiple doses of oral N-acetylcysteine in healthy Chinese and Caucasian volunteers: an open-label, Phase I clinical study.Adv Ther. 2021; 38: 468-478https://doi.org/10.1007/s12325-020-01542-4Crossref PubMed Scopus (15) Google Scholar and approximately 15 μmol/l with 600 mg (sustained-release formulation, Jarrow Formulas, time to reach Cmax at ∼110 minutes).32Nolin T.D. Ouseph R. Himmelfarb J. McMenamin M.E. Ward R.A. Multiple-dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease.Clin J Am Soc Nephrol. 2010; 5: 1588-1594https://doi.org/10.2215/CJN.00210110Crossref PubMed Scopus (29) Google Scholar For a research-related gelatin capsule formulation, a low Cmax of 2.5 μmol/l with 1200 mg NAC indicated a comparatively low bioavailability of this preparation.24Sandilands E.A. Rees J.M.B. Raja K. et al.Acetylcysteine has No Mechanistic Effect in Patients at Risk of Contrast-Induced Nephropathy: A Failure of Academic Clinical Science.Clin Pharmacol Ther. 2022; 111: 1222-1238https://doi.org/10.1002/cpt.2541Crossref PubMed Scopus (4) Google Scholar The effect of repeated dosing in healthy subjects is not entirely elucidated. A study with 600 mg NAC twice daily for 6 days (effervescent tablet, Mucomyst, Tika30Borgström L. Kågedal B. Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man.Biopharm Drug Dispos. 1990; 11: 131-136https://doi.org/10.1002/bdd.2510110205Crossref PubMed Scopus (55) Google Scholar) did not detect a change in Cmax for total NAC. In contrast, a study with 600 mg NAC twice daily for 6 days (uncoated tablets, Fluimucil, Zambon31Papi A. Di Stefano A.F.D. Radicioni M. Pharmacokinetics and safety of single and multiple doses of oral N-acetylcysteine in healthy Chinese and Caucasian volunteers: an open-label, Phase I clinical study.Adv Ther. 2021; 38: 468-478https://doi.org/10.1007/s12325-020-01542-4Crossref PubMed Scopus (15) Google Scholar) observed a Cmax increase. In addition, a study that analyzed free plasma NAC reported a significant increase for Cmax with 10 days of 600 mg NAC daily (Fluimucil sachets, Zambon33Maddock J. Biological properties of acetylcysteine: assay development and pharmacokinetic studies.Eur J Respir Dis Suppl. 1980; 111: 52-58PubMed Google Scholar). In patients with CKD G5 on dialysis therapy, the plasma concentrations after oral dosing were pronouncedly higher than in healthy subjects. The Cmax for total NAC after a single dose was approximately 63 μmol/l with 600 mg and approximately 125 μmol/l with 1200 mg NAC (sustained-release formulation, Jarrow Formulas, time to reach Cmax at ∼160–180 minutes).32Nolin T.D. Ouseph R. Himmelfarb J. McMenamin M.E. Ward R.A. Multiple-dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease.Clin J Am Soc Nephrol. 2010; 5: 1588-1594https://doi.org/10.2215/CJN.00210110Crossref PubMed Scopus (29) Google Scholar In another study, the administration of 600 mg NAC twice daily for 8 weeks to patients receiving peritoneal dialysis treatment increased the NAC plasma concentration from 2.6 to 24.8 μmol/l.34Nascimento M.M. Suliman M.E. Silva M. et al.Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo-controlled study.Perit Dial Int. 2010; 30: 336-342https://doi.org/10.3747/pdi.2009.00073Crossref PubMed Scopus (95) Google Scholar In healthy subjects, after i.v. administration of 200 mg NAC over 1 minute, a Cmax of approximately 121 μmol/l total NAC was obtained. After 4 hours, more than 50% of NAC was covalently bound to plasma proteins.29Olsson B. Johansson M. Gabrielsson J. Bolme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine.Eur J Clin Pharmacol. 1988; 34: 77-82https://doi.org/10.1007/BF01061422Crossref PubMed Scopus (277) Google Scholar In patients with CKD G3 and higher, without kidney replacement therapy (KRT), maximal NAC concentrations were observed approximately 5 minutes after an i.v. administration over 15 minutes. NAC concentrations increased dose-linearly, reaching a Cmax of approximately 430 μmol/l with 150 mg/kg NAC, and 2000 μmol/l with 450 mg/kg.35Dósa E. Heltai K. Radovits T. et al.Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency.Fluids Barriers CNS. 2017; 14: 26https://doi.org/10.1186/s12987-017-0075-0Crossref PubMed Scopus (17) Google Scholar In patients with CKD G5 and dialysis therapy, the steady-state NAC concentration was obtained at the fourth dose with repeated postdialyzer infusions of 2 g NAC during the first 3 hours of each hemodialysis session (3 sessions/wk). These steady-state concentrations reached 86 to 104 μmol/l; the Cmax of 325 μmol/l was obtained directly after infusion.36Soldini D. Zwahlen H. Gabutti L. Marzo A. Marone C. Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients.Eur J Clin Pharmacol. 2005; 60: 859-864https://doi.org/10.1007/s00228-004-0850-0Crossref PubMed Scopus (23) Google Scholar In healthy subjects, the distribution volume in the steady state of total NAC was reported as 0.47 l/kg, and plasma clearance was 0.11 l/h/kg. The terminal half-life was about 6 hours.29Olsson B. Johansson M. Gabrielsson J. Bolme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine.Eur J Clin Pharmacol. 1988; 34: 77-82https://doi.org/10.1007/BF01061422Crossref PubMed Scopus (277) Google Scholar Another study reported a clearance of 0.86 l/h/kg.31Papi A. Di Stefano A.F.D. Radicioni M. Pharmacokinetics and safety of single and multiple doses of oral N-acetylcysteine in healthy Chinese and Caucasian volunteers: an open-label, Phase I clinical study.Adv Ther. 2021; 38: 468-478https://doi.org/10.1007/s12325-020-01542-4Crossref PubMed Scopus (15) Google Scholar The half-life was between 15 and 19 hours, and the fraction of NAC excreted through the kidney within 36 hours after administration was approximately 4%. Finally, a study reported the excretion for nonprotein bound NAC by the kidney as approximately 30% of total body clearance.37Borgström L. Kågedal B. Paulsen O. Pharmacokinetics of N-acetylcysteine in man.Eur J Clin Pharmacol. 1986; 31: 217-222https://doi.org/10.1007/BF00606662Crossref PubMed Scopus (305) Google Scholar In patients receiving acute hemodialysis either for paracetamol poisoning or kidney impairment related to acute liver failure, dialytic clearances were reported. They were 0.11 l/h/kg (blood flow 300 ml/min)38Hernandez S.H. Howland M. Schiano T.D. Hoffman R.S. The pharmacokinetics and extracorporeal removal of N-acetylcysteine during renal replacement therapies.Clin Toxicol (Phila). 2015; 53: 941-949https://doi.org/10.3109/15563650.2015.1100305Crossref PubMed Scopus (13) Google Scholar and 0.18 to 0.3 l/h/kg (blood flow 400 ml/min, dialysate flow 800 ml/min; Fresenius Optiflux 200 and Asahi Kasei Medical, RX18AX dialyzers39Sivilotti M.L. Juurlink D.N. Garland J.S. et al.Antidote removal during haemodialysis for massive acetaminophen overdose.Clin Toxicol (Phila). 2013; 51: 855-863https://doi.org/10.3109/15563650.2013.844824Crossref PubMed Scopus (25) Google Scholar). The mean NAC extraction was 51% and 73% to 87 %, respectively. For continuous venovenous hemofiltration, we identified only 1 report, which found no significant NAC extraction.38Hernandez S.H. Howland M. Schiano T.D. Hoffman R.S. The pharmacokinetics and extracorporeal removal of N-acetylcysteine during renal replacement therapies.Clin Toxicol (Phila). 2015; 53: 941-949https://doi.org/10.3109/15563650.2015.1100305Crossref PubMed Scopus (13) Google Scholar In patients with CKD G5 and dialysis therapy, a 90% reduction of total body clearance for total plasma NAC after a single oral dose of 600 and 1200 mg was found in patients with chronic hemodialysis therapy (CKD G5: ∼0.06 l/h/kg, healthy: ∼0.8 l/h/kg).32Nolin T.D. Ouseph R. Himmelfarb J. McMenamin M.E. Ward R.A. Multiple-dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease.Clin J Am Soc Nephrol. 2010; 5: 1588-1594https://doi.org/10.2215/CJN.00210110Crossref PubMed Scopus (29) Google Scholar This cannot be explained by the reduction in renal clearance alone, which accounts for between 4% and 30% of total body clearance. It is well-known that nonrenal clearance too is impaired in advanced kidney disease. Protein binding of NAC to serum albumin is increased in kidney failure.40Harada D. Anraku M. Fukuda H. et al.Kinetic studies of covalent binding between N-acetyl-L-cysteine and human serum albumin through a mixed-disulfide using an N-methylpyridinium polymer-based column.Drug Metab Pharmacokinet. 2004; 19: 297-302https://doi.org/10.2133/dmpk.19.297Crossref PubMed Scopus (30) Google Scholar In addition, uptake in cellular compartments could be altered. The terminal half-life in CKD G5 was reported as 35 to 51 hours, representing a 12-fold increase compared to healthy controls.32Nolin T.D. Ouseph R. Himmelfarb J. McMenamin M.E. Ward R.A. Multiple-dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease.Clin J Am Soc Nephrol. 2010; 5: 1588-1594https://doi.org/10.2215/CJN.00210110Crossref PubMed Scopus (29) Google Scholar Likewise, a low total body clearance of approximately 0.02 l/h/kg was reported in another study in CKD G5.36Soldini D. Zwahlen H. Gabutti L. Marzo A. Marone C. Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients.Eur J Clin Pharmacol. 2005; 60: 859-864https://doi.org/10.1007/s00228-004-0850-0Crossref PubMed Scopus (23) Google Scholar The dialytic clearance when infusing NAC i.v. after the dialyzer was measured as approximately 0.07 l/h/kg in patients with chronic hemodialysis therapy (blood flow 250 ml/min; dialysate flow 500 ml/min, Fresenius F8 polysulfone dialyzer).36Soldini D. Zwahlen H. Gabutti L. Marzo A. Marone C. Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients.Eur J Clin Pharmacol. 2005; 60: 859-864https://doi.org/10.1007/s00228-004-0850-0Crossref PubMed Scopus (23) Google Scholar Pharmacokinetic parameters have been compiled in Table 1.Table 1Pharmacokinetic parameters for total NACPharmacokinetic parametersHealthy, NAC p.o.CKD G5, dialysis, NAC p.o.Healthy, NAC i.v.CKD, no KRT, NAC i.v.CKD G5, dialysis, NAC i.v.Bioavailability (%)∼10–100100100Cmax14–17 μmol/l with 600 mg63 μmol/l with 600 mg121 μmol/l with 200 mg (applied over 1 min)430 μmol/l with 150 mg/kg and 2000 μmol/l with 450 mg/kg over 15 min325 μmol/l with 2 g during 3 h of dialysistmax40–70 min after administration; 110 min with sustained release formulation160 min after administration with sustained release formulation∼at administrationmeasured 5 min after administrationat end of administrationRepeated dosingAccumulation possibleAccumulation was shown––Accumulation was shownTime to steady state with repeated dosing––––from 4th dose with 3 dialysis sessions/wkTotal body clearance0.1–0.9 l/h/kg0.02–0.06 l/h/kg,Dialytic clearance 0.07 l/h/kg0.1–0.9 l/h/kg–0.02–0.06 l/h/kg, dialytic clearance 0.07 l/h/kgCKD G5, last stage of chronic kidney disease, it requires KRT for survival; CKD, chronic kidney disease; Cmax, maximal plasma concentration; i.v., intravenous administration; KRT, kidney replacement therapy; NAC, N-acetylcysteine; p.o., oral administration; tmax, time to reach Cmax.The table gives estimates for typical populations. Differences are especially observed with varying oral NAC dosage forms, velocity of i.
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