Evaluation of the in vitro and in vivo performance of two sustained-release lithium carbonate matrix tablets, effect of different diets on the bioavailability

Two sustained-release (SR) lithium carbonate (Li) matrix tablets, which use a hydrophilic (HP) matrix of hydroxypropylmethylcellulose (Methocel 4K MP) and a lipid (L) matrix of hydrogenated castor oil (Cutina HR) as sustainin g agents, have been studied In vitro performance through dissolution tests in different media was established. The L and HP formulations were affected by the composition of the dissolution media, and liberation was complete i n 8 hr using a variable-pH medium that simulates the gastrointestinal (Gl)p H. Liberation was better described by the diffusional model of the square r oot of time for the L matrix and by zero-order kinetics for the HP matrix. Absolute bioavailability (BA) and food-induced changes on BA of both formul ations were studied The in vivo study design was a 4 X 4 Latin square invol ving 12 subjects who received two tablets of a 300-mg dose of SR formulatio ns while fasting or with a standardized normal, high-fat, or high-fat/high- protein meal. The results for both formulations showed no differences in th e disposition parameters and mean residence rime when the tablets were admi nistered with any type of diet. Changes in rate of absorption were found wh en both types of tablets were administered with any class of diet. The anal ysis of the ratio C-max/AUC (area under the curve) evidenced that changes i n C-max were attributable to a higher rate of absorption for the HP matrix and to a higher amount absorbed for the L matrix. In the last, high-fat and high-fat/high-protein diets produced higher AUCs than under fasting condit ion. The SR Li tablets formulated with hydrogenated castor oil were affecte d mor-e by high-fat food, probably because of the increase of pancreatic an d biliary secretions promoted by the meal, which would affect the matrix it self: The HP matrix was also affected but to a lesser extent. The magnitude of the change in C-max observed with this matrix probably is not important from a clinical point of view. Absolute BA was very low for the lipid matr ix; in addition, since it is more seriously affected by food, probably it i s not a good choice for a drug such as lithium. The in vivo behavior of the HP matrix makes it advisable to invest in efforts to achieve increased BA. Comparing in vitro and in vivo results, the focus should be achieving sust ained bur complete, in vitro liberation in not more than 3 hr, with simulat ion of the transit time through the stomach and small bowel since lithium i on is only absorbed to this point.