Enantioselective Effect of Flurbiprofen on Lithium Disposition in Rats.

AIMS: Lithium is administered for treating bipolar disorders and is mainly excreted into urine. Nonsteroidal anti-inflammatory drugs inhibit this process. In this study, we examined the enantioselective effect of flurbiprofen on the disposition of lithium in rats. METHODS: Pharmacokinetic experiments with lithium were performed. RESULTS: Until 60 min after the intravenous administration of lithium chloride at 30 mg/kg as a bolus, 17.8% of lithium injected was recovered into the urine. Its renal clearance was calculated to be 1.62 mL/min/kg. Neither creatinine clearance (Ccr) nor pharmacokinetics of lithium was affected by the simultaneous injection of (R)-flurbiprofen at 20 mg/kg. (S)-flurbiprofen impaired the renal function and interfered with the urinary excretion of lithium. The ratio of renal clearance of lithium to Ccr was decreased by the (S)-enantiomer. CONCLUSION: This study clarified that the (S)-flurbiprofen but not (R)-flurbiprofen inhibited the renal excretion of lithium in rats.

Temporal association as a prerequisite factor of valsartan-induced lithium toxicity.

OBJECTIVES: Lithium is often the mood stabilizer of choice for the treatment of type I bipolar disorder. However, side effects as well as the narrow therapeutic dosing range often complicate its use. Lithium toxicity can be fatal and its serum level needs to be closely monitored, especially at the time of introduction and titration, or whenever combined with potentially interacting drugs, such as inhibitors of angiotensin-converting enzyme (ACE-I) or angiotensin receptor 1 (AT1 ) blockers. ACE-I and AT1 blockers can increase serum lithium levels, leading to acute lithium toxicity upon their introduction or titration. METHODS: Here, we report a case of lithium toxicity during concomitant treatment with valsartan, an AT1 blocker, in a patient who previously displayed a stable serum lithium level. The patient was observed for a few weeks and the serum lithium concentration was measured regularly. RESULTS: In contrast to previous reports, the toxicity in our patient occurred not upon introduction or titration of lithium or valsartan but after subtle modifications in daily dosing schedule for lithium. Just before the onset of toxicity, lithium had been split into two doses, whereby half of the lithium daily dose was administrated concomitantly with valsartan. We presumed that this combination had led to simultaneous concentration peaks of valsartan and lithium, promoting lithium retention within a sharp time window. CONCLUSIONS: Our observation points to the need for caution not only during the introduction and titration of ACE-I/AT1 blockers in lithium-treated patients, but also whenever the temporal pattern of drug administration is modified.

Minor contribution of biliary excretion in lithium elimination in rats.

BACKGROUND: Lithium, which is often used for the treatment of bipolar disorders, is mainly recovered into urine after being orally administered. Due to the fact that it is completely absorbed via the gastrointestinal tract, it remains unknown whether biliary excretion is involved in the lithium disposition. In this study, we examined biliary excretion of lithium in rats and compared these with renal excretion. MATERIALS AND METHODS: After the injection of lithium chloride to femoral vein, plasma levels and excretion into urine and bile of lithium were evaluated. RESULTS: After its intravenous administration as a bolus, the plasma concentration of lithium decreased time-dependently. Until 60 min, 6.47% and 0.694% of injected lithium were excreted into urine and bile, respectively. The biliary clearance of lithium was calculated to be 0.0779 mL/min/kg, and this was 11.3% of the renal clearance. CONCLUSIONS: These findings suggest the low ability of the liver to eliminate lithium from plasma in comparison with the kidney in rats.

Time course of the renal functional response to partial nephrectomy: measurements in conscious rats.

Previous investigations into the functional responses of the surviving nephrons following reductions in renal mass have been performed largely in anaesthetized animals and have taken little account of how the compensatory changes develop with time. The present study has assessed a method for determining glomerular filtration rate (GFR) in unrestrained, uncatheterized, conscious rats (plasma disappearance of (99m)Tc-diethylenetriamene pentaacetic acid (DTPA)) and has used this method to document the time course of the changes in GFR over a 32 day period following uninephrectomy or 5/6 nephrectomy. Concurrent measurements of excretion rates and of the clearance of lithium (the latter being an index of end-proximal fluid delivery) provided information on changes in overall tubular function and segmental reabsorption. After uninephrectomy, the GFR of the remaining kidney (compared with that of a single kidney of sham-operated animals) increased maximally (by approximately 50%) within 8 days; after 5/6 nephrectomy, the increase in the GFR of the remnant kidney was maximal (at approximately 300%) within 16 days. Overall excretion rates of sodium and potassium were well maintained in partially nephrectomized animals throughout the period of study, while the excretion of water increased (by approximately 30% after uninephrectomy and by approximately 120% after 5/6 nephrectomy), partly as a result of the compensatory increases in GFR but mainly as a consequence of moderate (after uninephrectomy) or marked (after 5/6 nephrectomy) reductions in fractional reabsorption. During the early period after 5/6 nephrectomy, potassium excretion sometimes exceeded the filtered load, indicating net secretion. Lithium clearance data indicated that the changes in tubular function after 5/6 nephrectomy include a reduction in fractional reabsorption in the proximal tubule, whereas after uninephrectomy any such effect on the proximal tubule is minor and transient.