Pharmacokinetics of cysteamine bitartrate following intraduodenal delivery

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 naive 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 naive. Following intraduodenal cysteamine (20mg/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 C-max was achieved in 5-10min from PV and 5-22.5min from JVC. The PV-C-max (P=0.08), PV-AUC(0-t) (P=0.16), JVC-C-max (P=0.02) and JVC-AUC(0-t) (P=0.03) were higher in naive than in pretreated animals. Plasma cysteamine levels returned to baseline in <= 120min. The hepatic first-pass effect was estimated at 40%. Peak tissue and CSF cysteamine levels occurred <= 22.5min, but returned to baseline levels <= 180min. There was no difference in CSF and tissue cysteamine levels between naive 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 2h after ingestion. Sustained-release cysteamine may provide prolonged tissue exposure.