Pharmacokinetics of cysteamine bitartrate following intraduodenal delivery

Abstract

Cysteamine is approved for the treatment of cystinosis and is being evaluated for Huntington's disease and non-alcoholic fatty liver disease. Little is known about the bioavailability and biodistribution of the drug. The aim was to determine plasma, cerebrospinal fluid (CSF), and tissue (liver, kidney, muscle) cysteamine levels following intraduodenal delivery of the drug in rats pretreated and naïve to cysteamine and to estimate the hepatic first-pass effect on cysteamine. Healthy male rats (n = 66) underwent intraduodenal and portal (PV) or jugular (JVC) venous catheterization. Half were pretreated with cysteamine, and half were naïve. Following intraduodenal cysteamine (20 mg/kg), serial blood samples were collected from the PV or the JVC. Animals were sacrificed at specific time points, and CSF and tissue were collected. Cysteamine levels were determined in plasma, CSF, and tissue. The Cmax was achieved in 5-10 min from PV and 5-22.5 min from JVC. The PV-Cmax (P = 0.08), PV-AUC0-t (P = 0.16), JVC-Cmax (P = 0.02) and JVC-AUC0-t (P = 0.03) were higher in naive than in pretreated animals. Plasma cysteamine levels returned to baseline in ≤120 min. The hepatic first-pass effect was estimated at 40%. Peak tissue and CSF cysteamine levels occurred ≤22.5 min, but returned to baseline levels ≤180 min. There was no difference in CSF and tissue cysteamine levels between naïve and pretreated groups, although cysteamine was more rapidly cleared in the pretreated group. Cysteamine is rapidly absorbed from the small intestine, undergoes significant hepatic first-pass metabolism, crosses the blood brain barrier, and is almost undetectable in plasma, CSF, and body tissues 2 h after ingestion. Sustained-release cysteamine may provide prolonged tissue exposure.

Human and animal fertility studies in cystinosis reveal signs of obstructive azoospermia, an altered blood‐testis barrier and a subtherapeutic effect of cysteamine in testis

“…Similar levels of cysteamine in the kidney were achieved following intraduodenal administration in rats. Likewise, plasma levels were similar to those observed in mice injected intraperitoneally 15 . This suggests that the cysteamine dose used in this study is subtherapeutic for the testes which is likely to be the case in cystinosis patients, which could, in turn, explain the lack of effect of cysteamine on the development of gonadal failure.…”

“…Tissue cystine levels were evaluated in the Laboratory of Metabolic Biochemistry Unit, Department of Pediatric Medicine, Bambino Gesù Children's Hospital, Rome, Italy, with modifications from the method that was published earlier 13,14 . In addition, plasma and tissue cysteamine levels were evaluated in the UCSD Biochemical Genetics and Metabolomics Laboratory, University of California San Diego, as was published earlier 15 …”

In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores

“…However, ensuring an adequate supply of precursor amino acids, especially cysteine, to support intracellular glutathione synthesis is a proven strategy for preventing glutathione depletion in the liver 12, 13 . Cysteamine is a small molecule (HS-CH 2 -CH 2 -NH 2 ) which is able to cross cell membranes easily and reacts with extracellular cystine to form cysteine which is then readily taken up into cells and used to support glutathione synthesis 14–16 . In an open-label pilot study, 6 months of treatment with cysteamine bitartrate improved serum alanine (ALT) and aspartate aminotransferase (AST) levels and increased adiponectin in children with NAFLD 17 .…”

Pharmacokinetic Studies of Cysteamine Bitartrate Delayed‐Release

“…Secondly, a recent study in rats has shown that cysteamine absorption is greater in naïve than in animals pre-treated with cysteamine (ref. 25 to follow). Better absorption in the Naïve group may be explained by a recent animal study which reports that cysteamine uptake from the intestinal tract is a saturable carrier-mediated process that involves organic cationic transporters.…”

“…Firstly, cysteamine absorption is greater when drug is taken during fasting than with high fat diet. Secondly, a recent study in rats has shown that cysteamine absorption is greater in naïve than in animals pre‐treated with cysteamine (ref . to follow).…”