Vitreous pharmacokinetics and bioavailability of memantine after subtenon, intravenous, and intravitreal administration in rabbits.

PURPOSE: This study evaluated the vitreous pharmacokinetics and vitreous bioavailability of memantine following posterior-subtenon administration (PST) compared to intravitreal (INT) and intravenous routes (INV) in rabbits. METHODS: Vitreous pharmacokinetic analysis was performed on female New Zealand (NZ) albino rabbits after PST, INT, and INV administration and calculating the pharmacokinetic parameters that describe memantine vitreous distribution. The vitreous bioavailability (F) and the relative vitreous bioavailability of memantine was estimated after posterior-subtenon administration (Frel (pst/int)) and after intravenous route (Frel (inv/int)) compared with intravitreal administration. Relative vitreous bioavailability of memantine was also estimated following PST administration compared with vitreous concentrations after intravenous administration (Frel (pst/inv)). RESULTS: Memantine kinetics in the vitreous of NZ albino rabbits after PST administration can be explained by a one-compartment model, which was characterized by a fast absorption process, and a short terminal half-life. Vitreous pharmacokinetics following INV administration was also characterized by a fast absorption process, a terminal half-life significantly longer than the subtenon route, and low area under the curve values. High vitreous bioavailability after PST was observed, and the relative vitreous bioavailability of memantine following PST administration (0.53%) was greater than for intravenous administration (0.02%). CONCLUSIONS: Our results suggest that memantine reaches the vitreous after PST administration by local diffusion. These data also show that local diffusion of the drug is responsible for greater vitreous availability of memantine following PST administration compared with INV administration.

Cysteinemia, rather than homocysteinemia, is associated with plasma apolipoprotein A-I levels in hyperhomocysteinemia: lipid metabolism in cystathionine beta-synthase deficiency.

OBJECTIVE: Genetic and dietary hyperhomocysteinemia has been found to decrease high density lipoproteins (HDL) and their apolipoprotein A1 (APOA1). To test the hypothesis that the presence of cysteine could normalize HDL levels in hyperhomocysteinemic cystathionine beta-synthase (Cbs)-deficient mice and that the inclusion of glycine would block this effect. METHODS: Lipids and HDL cholesterol were studied in Cbs-deficient mice and wild-type animals fed a low-methionine diet supplemented with cysteine and glycine and in Cbs-deficient mice on the same diet supplemented only with cysteine. RESULTS: Triglyceride and homocysteine levels were significantly decreased and increased, respectively in Cbs-deficient mice irrespective of treatment. However, plasma cholesterol, glucose and APOA1 were significantly decreased in homozygous Cbs-deficient mice when they received the cysteine and glycine-enriched beverage. This group of mice also showed decreased mRNA levels and increased hepatic content of APOA1 protein, the latter increase was observed in endothelial cells. A significant, inverse relationship was observed between plasma and hepatic APOA1 concentrations while a positive one was found between plasma levels of cysteine and APOA1. CONCLUSION: These data suggest an altered hepatic management of APOA1 and that cysteine may be involved in the control of this apolipoprotein at this level. Overall these findings represent a new aspect of dietary regulation of HDL at the hepatic transendothelial transport.