Population Pharmacokinetic Model of N-Acetylcysteine During Periods of Recurrent Hypoglycemia in Healthy Volunteers.

Autor: Fayed MS; Department of Clinical Pharmacy, College of Pharmacy, Ain Shams University, Cairo, Egypt., Brooks J; Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA., Seaquist ER; Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Kumar A; Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Moheet A; Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Eberly L; Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA., Mishra U; Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA., Coles LD; Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2023 Dec; Vol. 12 (12), pp. 1234-1240. Date of Electronic Publication: 2023 Nov 08.
DOI: 10.1002/cpdd.1338
Abstrakt: Recurrent hypoglycemia leads to impaired awareness of hypoglycemia where the blood glucose threshold that elicits the counterregulatory response is lowered. Hypoglycemia-induced oxidative stress is hypothesized to contribute to impaired awareness of hypoglycemia development and hypoglycemia-associated autonomic failure. Our group conducted a randomized, double-blinded, placebo-controlled, crossover study in healthy individuals undergoing experimentally induced recurrent hypoglycemia to evaluate the impact of intravenous N-acetylcysteine (NAC) during experimental hypoglycemia to preserve the counterregulatory response to subsequent hypoglycemia. The work presented herein aimed to characterize the NAC pharmacokinetics and its effects on oxidative stress. Whole blood and plasma samples were collected at specified time points during separate NAC and placebo infusions from 10 healthy volunteers. Samples were analyzed for NAC, cysteine, and glutathione (GSH) concentrations. A 2-compartment population NAC pharmacokinetic model was developed. Estimates for central compartment clearance and volume of distribution were 19.8 L/h, and 12.2 L, respectively, for a 70-kg person. Peripheral compartment clearance and volume of distribution estimates were 34.9 L/h and 13.1 L, respectively, for a 70-kg person. The PK parameters estimated here were different from those reported in the literature, suggesting a higher NAC clearance during hypoglycemic episodes. NAC leads to a significant increase in circulating cysteine concentration in a NAC concentration-dependent manner, suggesting rapid biotransformation. A transient decrease in plasma GSH was observed, supporting the hypothesis that NAC can act as a reducing agent displacing glutathione from the disulfide bond allowing for increased clearance and/or distribution of GSH.
(© 2023 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
Databáze: MEDLINE
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