Population pharmacokinetic modeling of sustained release lithium in the serum, erythrocytes and urine of patients with bipolar disorder.

PURPOSE: Lithium (Li), the first-line treatment of bipolar disorder, was first developed as an immediate-release form with a routine therapeutic drug monitoring 12 h after the last dose. In Europe, the most commonly prescribed form is a sustained release (srLi). Yet no pharmacokinetics (PK) study has been published of srLi, administered once a day, in adults. The present study describes srLi PK in the serum and erythrocytes of bipolar patients. METHODS: To assess srLi PK, we studied prospectively 17 French bipolar patients on a median dose of 1000 mg (600-1600) for at least 2 years. Serum (S), erythrocyte (E) concentrations, and urinary (U) amount were collected over 8 h after 15 days of morning intake using monitoring electronic medical system (MEMs). Population PK parameters were estimated using the SAEM algorithm (MONOLIX 4.3.3 software). RESULTS: Using a population approach, we built a PK population model of srLi including one S compartment (VS = 23.0 L, ClS = 1.21 L h-1), one E compartment (VE = 64.7 L, ClSE = 3.63 L h-1, ClES = 9.46 L h-1), and one U compartment (F = 0.62) and estimate the ratio of concentrations to Li in E over S at 0.38 with 27% between-subject variability. CONCLUSION: This is a PK model of srLi once a day in bipolar patients using a population approach simultaneously describing Li concentrations in serum, erythrocytes, and urine which provide an estimate of the ratio of concentration in erythrocyte over serum and its between-subject variability (BSV).

Pharmacokinetics of lithium in healthy volunteers after exposure to high altitude.

INTRODUCTION: Exposure of the human body to high altitude causes a number of physiological changes. In previous studies, we observed that these changes may alter the pharmacokinetics of drugs. The number of erythrocytes/mm3 increases both, after acute exposure to high altitude (HA), i.e. within 12 - 24 h after reaching high altitude (H), as well as in chronic exposure (HC) (> 10 months) to H. Also binding of drugs to biologic material may change with exposure to HA and/or HC. OBJECTIVE: Since lithium is transported into and out of erythrocytes and binds strongly to erythrocytes, but is not plasma protein-bound, we selected this drug as candidate for the present study. SUBJECTS, MATERIAL AND METHODS: Lithium carbonate 300 mg were administered orally to young healthy volunteers. One group residing at low altitude (Santiago, Chile, 600 m, group L), these same volunteers after 15 hours of exposure to high altitude (4,360 m, group HA), and volunteers living at high altitude for at least 10 months (group HC). RESULTS: We found a significant increase of both hematocrit and red blood cell count (RBC) after exposure to H, both, acute or chronic. Elimination half-life increased 64.1% in group HA and 111.4% in group HC in comparison to group L. We also found an increase in volume of distribution: + 18.9% in group HA, and + 35.8% in group HC when measured in plasma, and + 16.9% in group HA and + 18.8% in group HC when measured in whole blood. Lithium uptake by the erythrocytes increases: the value of 36.7 +/- 22.7% in Group L rose to 54.8 +/- 21.1% and to 54.6 +/- 24.2% in groups HA and HC, respectively. Total clearance decreases at high altitude, though the differences were significant only in group HC (37%). CONCLUSION: Results indicate that exposure to H produces alterations in the pharmacokinetics of lithium and that these variations may be clinically relevant.

Effect of an acute oral lithium intake on urinary Aquaporin-2 in healthy humans with and without simultaneous stimulation with hypertonic saline infusion.

OBJECTIVE: Animal experiments have shown that lithium interferes with the formation of Aquaporin-2 in the distal renal tubuli. The effect of lithium on formation of renal water channels has not been studied in healthy humans. The aim of this study was to test the hypotheses that a single oral dose of lithium will reduce the formation of water channels both with and without stimulation with hypertonic saline infusion, and that this effect can be detected by measurement of urinary excretion of Aquaporin-2 (u-AQP2). METHODS: In healthy subjects, Study 1 (n = 11) and Study 2 (n = 12), urine was collected in 6 and 7 periods between 08.00 and 14.00, respectively, and blood samples were drawn at 30- to 60-min intervals. The study medication was given at 09.00; u-AQP2 was determined by radioimmunoassay. RESULTS: In Study 1 neither u-AQP2 nor urinary output were significantly changed by lithium. In Study 2, u-AQP2 was increased by hypertonic saline infusion in parallel with an increase in arginine vasopressin. At the end of the study, u-AQP2 was increased by 30% with placebo but only by 13% with the 600 mg lithium dose, and urinary output was significantly higher after 600 mg lithium than after placebo and 300 mg lithium. CONCLUSIONS: U-AQP2 was not significantly changed after a single oral dose of lithium. The antidiuretic response to hypertonic saline infusion was reduced when lithium was given. It is suggested that lithium increases urinary output by inhibiting trafficking of renal water channels in healthy humans.

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.

Determination of discretionary salt intake in rural Guatemala and Benin to determine the iodine fortification of salt required to control iodine deficiency disorders: studies using lithium-labeled salt.

The use of discretionary salt, which is salt added during cooking and at the table, as a suitable vehicle for iodine intake was assessed by measuring salt consumption using the lithium-marker technique in rural areas of Guatemala and Benin. In both countries, we studied boys aged 6-12 y and their mothers. Subjects used lithium-labeled salt after all unlabeled salt was removed from their households. In Guatemala, 24-h urine samples for 9 mother-son pairs were collected at baseline and on days 7, 8, and 9 during the use of lithium-labeled salt. Total maternal salt intake averaged 5.2 +/- 1.7 g/d (mean +/- SD), of which 77 +/- 24% came from discretionary sources, whereas Guatemalan boys consumed 1.8 +/- 0.6 g salt/d, of which 72 +/- 12% came from discretionary sources. In Benin, urine collection from 13 mother-son pairs took place at baseline and on days 5 and 7. Beninese mothers had a total salt intake of 9.0 +/- 2.9 g/d and their sons had an intake of 5.7 +/- 2.8 g/d; discretionary salt contributed 52 +/- 14% and 50 +/- 13%, respectively, of total salt consumed. Therefore, fortification of household salt appears to be an appropriate method of controlling iodine deficiency in both countries, although fortification of other salt sources could be considered in Benin.

Tenidap sodium decreases renal clearance and increases steady-state concentrations of lithium in healthy volunteers.

1. An open-label, randomised placebo-controlled study was conducted to determine the effects of tenidap sodium, a novel, cytokine-modulating anti-rheumatic drug, on the steady-state concentrations and renal clearance of lithium carbonate. 2. Eighteen healthy male volunteers received 450 mg lithium carbonate twice daily for 15 days and once on day 16. On days 9-16 subjects also received either placebo or 120 mg day-1 tenidap 2 h prior to the morning dose of lithium. 3. Following a single dose of tenidap, the renal clearance of lithium decreased significantly by 0.36 l h-1 (-23%) compared with the clearance in the placebo group, which increased by 0.18 l h-1 (+14%). Steady-state serum lithium levels increased after a single dose of tenidap by 0.069 mEq l-1 (+13%), and in the placebo group levels increased by 0.003 mEq l-1 (+0.5%); this difference was not significant. 4. After 7 days' continuous administration of tenidap, the renal clearance of lithium had decreased by 0.38 l h-1 (-25%), compared with the placebo group in which clearance had increased by 0.16 l h-1 (+12%). The steady-state serum concentration of lithium increased by 0.208 mEq l-1 (+39%) in the tenidap group and by 0.063 mEq l-1 (+10%) in the placebo group. Both of these differences were significant. 5. Two subjects who received lithium plus tenidap experienced gastrointestinal side effects, compared with none of those who were administered lithium plus placebo. 6. It is recommended that serum lithium levels be monitored when tenidap and lithium are administered concomitantly.