Effect of three different diets on the bioavailability of a sustained release lithium carbonate matrix tablet.

BACKGROUND: Food-induced changes on the bioavailability of a sustained release lithium carbonate matrix tablet, which uses an acrylic matrix of Eudragit RSPM as sustaining agent, have been studied in healthy male volunteers. The tablet was developed in our laboratory using conventional technology. SUBJECTS, MATERIALS AND METHODS: The study design was a 4 x 4 Latin square involving 12 subjects who received a single dose of the tablet while fasting or with a standardized normal, high fat or high fat/high protein meal. RESULTS: The results showed no differences in half-lifebeta, renal clearance, Vdbeta, AUC, tmax, Xinfinite(u), fraction absorbed and MRT. Higher Cmax (mg/l) were obtained when the tablet was administered with any kind of meal: 2.09 +/- 0.47 (fast), 2.95 +/- 1.04 (normal diet), 2.64 +/- 0.54 (high fat diet) and 2.87 +/- 0.67 (high fat/high protein diet). The analysis of the ratio Cmax/AUC indicated that changes in Cmax were more probably due to changes in the rate of absorption. To evaluate if the magnitude of the change could be clinically relevant, Cmax and C at 12 hours (dosing interval) were treated by the superposition method in order to establish maximum and minimum concentrations at steady-state. For all the experimental conditions both concentrations would remain in the therapeutic range (4.2 10 mg/l or 0.6 - 1.4 mEq/l). CONCLUSION: The behavior of the formulation is appropriate for a sustained release tablet and fasting or non-fasting state seems not to be a major consideration for bioavailability when deciding on the regimen administration.

In vitro conditions for the study of the in vivo performance of sustained-release theophylline matrix tablets administered in fasted conditions and with a high-fat diet.

Dissolution profiles of theophylline (TP) from three types of sustained-release (SR) matrix tablets (plastic [PL], lipid [LP], and hydrophilic [HP]) in different dissolution media, with and without enzymes, were established. Also investigated was the influence of a treatment of the tablets with peanut oil prior to the dissolution test. The in vivo behavior of the tablets under the fasted state and with the concomitant administration with a high-fat diet was previously evaluated; the diet produced changes in the absorption profiles for the three matrix tablets in comparison with fasted administration. Level A correlations were obtained between cumulative percentage dissolved (CPD) and cumulative percentage absorbed (CPA). For the fasted condition, better correlations were obtained with water as the dissolution medium for the HP and LP matrix; for PL matrix, the best correlation was obtained with a medium with gradual change of pH. The pretreatment with peanut oil showed better correlations for the fed state.

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 sustaining 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 in 8 hr using a variable-pH medium that simulates the gastrointestinal (Gl) pH. Liberation was better described by the diffusional model of the square root 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 formulations were studied. The in vivo study design was a 4 x 4 Latin square involving 12 subjects who received two tablets of a 300-mg dose of SR formulations while fasting or with a standardized normal, high-fat, or high-fat/high-protein meal. The results for both formulations showed no differences in the disposition parameters and mean residence time when the tablets were administered with any type of diet. Changes in rate of absorption were found when both types of tablets were administered with any class of diet. The analysis of the ratio Cmax/AUC (area under the curve) evidenced that changes in Cmax 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 condition. The SR Li tablets formulated with hydrogenated castor oil were affected more by high-fat food, probably because of the increase of pancreatic and biliary secretions promoted by the meal, which would affect the matrix itself. The HP matrix was also affected, but to a lesser extent. The magnitude of the change in Cmax observed with this matrix probably is not important from a clinical point of view. Absolute BA was very low for the lipid matrix; in addition, since it is more seriously affected by food, probably it is 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 sustained, but complete, in vitro liberation in not more than 3 hr, with simulation of the transit time through the stomach and small bowel since lithium ion is only absorbed to this point.

The value of tissue polypeptide specific antigen TPS determination in serum of women with breast cancer comparison to mucin-like associated antigen MCA and CA 15-3 antigen.

The aim of the study was TPS diagnostic value determination in the serum of women with breast cancer as compared with MCA and CA 15-3. The relationship between the serum concentration of these antigens and patient age, clinical stage, histological grade, presence of metastases to lymph nodes and histological type of neoplasm was evaluated. Studies were conducted on the sera of 139 women before surgical procedure aged 28-81, treated in the Clinic of Oncology, at Karol Marcinkowski University of Medical Sciences in Poznan. The TPS concentration was determined using the "BEKI Diagnostics" immunoenzymatic method, MCA - by the "Roche" test and CA 15-3 concentration was determined by the "Abbott" immunofluorescent test. The study showed significantly higher levels of TPS, CA 15-3 and MCA in women with cancer, compared with values in healthy women and women with mastopathy. The highest median of concentration and frequency of occurrence was obtained for TPS. A correlation between enhancement of TPS and CA 15-3 concentration with clinical stage was observed. A similar connection was noted in women with metastases to the lymph nodes. Serum MCA concentration results did not demonstrate the above effects. The study suggests, that in estimating the clinical condition of women with breast cancer, the simultaneous determination of TPS with CA 15-3 seems to be a more useful prognostic factor than TPS or CA 15-3 with MCA.

The biochemical modification of the erythrocyte membranes from women with ovarian cancer.

The aim of our work was quantitative evaluation of the protein and phospholipid fractions of mature erythrocyte membranes separated from women with ovarian cancer. Blood was sampled from 30 women with ovarian cancer, aged 24-79 years, in the third stage of clinical progression of the disease. Phospholipids were separated from membranes by Müller's acidic extraction method and analysed in thin-layer two-dimensional chromatography. On the silica gel plates nine fractions of phospholipids were separated: sphingomyelin (SPH), phosphatidylethanolamine (PE), phosphatidlyserine (PS), phosphatidylcholine (PC), lysophosphatidylcholine (LPC), phosphatidic acid (PA), phosphatidylinositol (Ptd Ins), phosphatidylinositol-4-phosphate (Ptd Ins-4-P), phosphatidylinositol-4,5-diphosphate (Ptd Ins-4,5-P2). The activity of phospholipase C in erythrocyte membranes was determined by Akhrem's spectrophotometric method. Membrane proteins were separated by polyacrylamide gel electrophoresis, SDS-PAGE. It was shown that PS, SPH, LPC and PA fractions were significantly diminished. The concentration of Ptd Ins-4-P and Ptd Ins-4,5-P2 was significantly increased with simultaneous reduction in Ptd Ins level. The inhibition of phospholipase C reached 80%. The quantitative protein evaluation showed a statistically significant decrease in spectrin and a significant increase in 4.1 protein. The quantitative changes, observed in phospholipid and protein fractions, led to the restructuring of the erythrocyte membrane cytoskeleton, which may be connected to increased susceptibility to haemolysis of red blood cells.

Evaluation of the effect of 3 different diets on the bioavailability of 2 sustained release theophylline matrix tablets.

Food-induced changes on bioavailability of 2 sustained release theophylline matrix tablets, which uses an hydrophilic matrix of Carbopol 974P and lipid matrix of hydrogenated castor oil (Cutina HR) as sustaining agents, have been studied in 2 different groups of 12 healthy male volunteers. The study design was a 4 x 4 Latin square involving 12 subjects who received a single dose of the tablet while fasting or with a standarized normal, high fat or high fat/high protein meal. The results for both formulations showed no differences in t1/2 and MRT when the tablets were administered with any type of diet. No differences in tmax and AUC were found when the Carbopol matrix tablet was administered with any class of diet. Higher Cmax were obtained when the tablet was administered with any class of meal. The analysis of the ratio Cmax/AUC evidenced that changes in Cmax for normal and high fat diet were attributable to higher rate of absorption, probably due to a delay in gastric emptying, thus avoiding the rapid formation of the gel structure which controls the liberation of theophylline. Three subjects showed a probable bioadhesive behavior of the formulation in the fasted condition. The lipid matrix tablet showed a statistical significant delay in tmax comparing the fasted condition with the different diets. AUC, Cmax, and the ratio Cmax/AUC did not change when the tablet was administered with the normal diet. High fat and high fat/high protein diets produced higher AUC (31% and 40%, respectively) and Cmax (40% and 56%, respectively) than under fasting condition. The analysis of the ratio Cmax/AUC indicated that changes in Cmax were more probably due to changes in the amount absorbed. In conclusion, a sustained-release theophylline tablet formulated as a lipid matrix is affected by any meal with a high fat content, probably because of the increase of pancreatic and biliary secretions promoted by the meal that would affect the matrix itself. Normal diet showed this behavior but only as a nonsignificant trend. It seems appropiate to recommend to dose both formulations at least 2 hours before meal, or under consistent conditions of fasting or nonfasting state to assure reproducible absorption or clinical response.

Chronopharmacokinetics of theophylline administered as a controlled-release tablet.

The result obtained from different studies of the chronopharmacokinetics of some controlled-release tablets of theophylline are variable, since some authors report differences while others do not. At our laboratory we have developed a formulation of a controlled-release theophylline tablet using acrylic resins and we studied the chronopharmacokinetics of theophylline from this dosage form. Seven Caucasian healthy male volunteers participated in the study approved by the Institutional Review Board (IRB). Each volunteer received a controlled release tablet of 300 mg theophylline and an i.v. dose equivalent to 131.46 mg theophylline once at 8.00 a.m. and once at 8.00 p.m. Theophylline plasma concentrations were determined by HPLC. The following pharmacokinetic parameters were calculated: maximum concentration, time to reach maximum concentration, mean residence time, absorption constant, area under the curve of plasma concentration versus time, distribution volume (Vd beta), and total clearance. No statistically significant differences were found between diurnal and nocturnal data. This implied that, with this formulation, there is a lower risk of toxic plasma concentrations or concentrations under the therapeutic level than with formulations that exhibit circadian rhythm.

Evaluation of the effect of different kinds of foods on the bioavailability of a sustained-release theophylline tablet.

Food-induced changes on the bioavailability of a sustained-release theophylline tablet, which uses acrylic resins Eudragit as sustaining agent, were studied in 12 healthy male volunteers. The tablet was developed in our laboratory using conventional technology. It presented a good bioavailability pattern and maintained plasmatic concentrations within the therapeutic range for 12 hours under conditions of steady-state. The study design was a 4 x 4 latin square involving 12 subjects who received a single dose of the tablet while fasting or with a standardized normal, high fat or high fat/high protein meal. The results showed no differences in AUC, K, tmax, ka and MRT. Statistical differences were found in Cmax comparing the fasting condition with high fat/high protein diet. A delay was also observed in the detection of the drug in plasma when the tablet was administered with high fat and high fat/high protein food, but clinically the changes seem to be irrelevant.