Investigation on Pharmacokinetics of Meloxicam in Dialysis Patients

Abstract

Considering that dialysis patients are often elderly, the onset risk of gastric mucosa disorder is increased in them. Therefore, the use of a selective cyclooxigenase (COX)-2 inhibitor that is expected to reduce the digestive disorders in the dialysis patients is of great significance. We investigated pharmacokinetics of meloxicam which is a selective COX-2 inhibitor approved in over 100 countries including Japan. Nine renal patients (4 males and 5 females) on hemodialysis were investigated. Single oral administration of meloxicam was conducted after supper the day before dialysis and plasma consentration was determined. The blood was taken at 1 hour, before start of dialysis. The meloxicam concentration was analysed by ultrafiltration. The mean plasma meloxicam concentration (meant-SD) at 1 hour before start of dialysis and at 1, 4 and 48 hours after the start of dialysis were 541±168 ng/ml, 532±153, 512± 161, 42± 72, respectively. The results indicated not significant changes in the plasma concentration at 1 and 4 hours after start of dialysis. Introduction Disorders in motor organs are sometimes caused in patients on long term hemodialysis due to amyloidosis derived from f32 microglobulin. As many of dialysis patients are elderly, they often complain arthritis and other diseases that occur in association with aging. As a result, these patients have to be often treated with nonsteroidal anti-inflammatory drugs (NSAIDs). In this regard, it is important to evaluate the influence of dialysis on the pharmacokinetics of an NSAID to be administered. We have investigated the pharmacokinetic profile of meloxicam in dialysis patients. Meloxicam was approved in December 2000 in Japan as an NSAID with selective COX-2 inhibition. NSAIDs demonstrate anti-inflammatory and analgesic effect by inhibiting prostaglandin through its potent inhibition on COX. The presence of 2 isozymes of COX, namely COX1 and COX-2, was discovered in the beginning of 19901). COX-1 is considered to constructively occur in normal cells and is involved in the maintenance of gastric and renal functions. On the other hand, COX2 is induced by inflammatory cells and is involved in the production of prostaglandin that enhances the inflammation and pain2)3). Since conventional NSAIDs inhibit both COX-1 and COX-2, they might cause digestive and renal disorders While they demonstrate anti-inflammatory and analgesic effect. However, selective COX-2 inhibitors such as meloxicam have less influence on COX-1 that is related to gastric and renal functions while it strongly inhibits COX-2 that is involved in inflammation. Accordingly, these drugs are expected to demonstrate strong anti-inflammatory and analgesic effect while their influence on the stomach and kidney is negligible. Considering that dialysis patients are often elderly, the onset risk of gastric mucosa disorder is increased in them. Therefore, the use of a selective COX-2 inhibitor that is expected to reduce the digestive disorders in the dialysis patients is of great significance. Subjects and Methods Subjects Nine renal failure patients (4 males and 5 females) on hemodialysis were investigated. The mean age of patients was 67.9 years old (51-85 years old). The duration of dialysis was 4 hours. The blood flow rate was maintained at 200 ml/min and the dialysate flow rate was set at 500 ml/mm. The dialyzer was used manufactured by Kawasumi Laboratory Inc. (KF-10C EVAL membrane) and its dialysis area was 1.0 m2. Methods Single oral administration of meloxicam at 10 mg was conducted after supper the day before dialysis and the plasma concentration was determined. The blood was taken at 1 hour before the start of dialysis, and at 1, 4 and 48 hours after the start of dialysis. The collected blood was rapidly centrifuged and the plasma obtained was preserved at -20°C until the time of analysis. Assay The meloxicam concentration was analyzed by ultrafiltration. The metabolites were analyzed by high performance liquid chromatography. The plasma was made acidic with 2.3 m1/1 citrate and extracted with dichloromethane. The internal standard substance was added to this to extract meloxicam. For collection of extract, 0.2 mol/1 sodium hydroxide was used. Results After single administration of 10 mg of meloxicam, the plasma concentration was determined at each point before and after hemodialysis (Table 1). The plasma meloxicam concentrations (mean±SD) at 1 hour before the start of dialysis, and at 1, 4 and 48 hours after the start of dialysis were 541 ± 168 ng/ ml, 532± 153, 512±161 and 47±72. The changes were investigated by statistical analysis (paired ttest for comparison of 2 groups) (Fig. 1). The results did not indicate significant changes in the plasma concentration at 1 and 4 hours after the start of dialysis in comparison with that at 1 hour before the start of dialysis. However, the plasma concentration after 48 hours significantly decreased (p<0.001). Of the 9 patients investigated, the plasma concentration at 48 hours after the start of dialysis decreased to a level below the quantitative limit in 6 and to 100 ng/ml or so in the remaining 3. abroad after single administration of meloxicam at 15 mg. One of the reasons why the drug did not accumulate even though it was not dialyzed is that about 47% of the drug (after 180 hours after administration) was excreted into stools6). The above pharmacokinetic profile indicates meloxicam is not much restricted by dialysis. No adverse reaction assumed to be attributable to meloxicam was observed during the study period. Discussion After single administration at 10 mg, the plasma concentration of meloxicam at 1 hour and 4 hours after the start of dialysis did not demonstrate any significant difference in comparison with the concentration before dialysis. The result indicates that meloxicam is less influenced by the dialysis. The plasma meloxicam concentration significantly decreased at 48 hours after the start of dialysis, indicating no accumulation. These results correspond with the pharmacokinetic results obtained from the dialysis patients References 1) Xie, W, Chipman, J. G. and Robertson, D. L.: Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Nat! Acad Sci USA, 88: 2692-2696, 1991. 2) Moncada, S., Gryglewski, R. and Bunting, S.: An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature, 263: 663-665, 1976. 3) Dewitt, D. L.: Prostaglandin endoperoxide synthase; regulation of enzyme expression. Biochim Biophys Acta, 1083: 121-134, 1991. 4) Pariet, M. and Ryn, J. V.: Experimental models used to investigate the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2 by non-steroidal antiinflammatory drugs. Inflamm Res, 47(Suppl. 2): S293— 101, 1998. 5) Truck, D., Schwarz, A., Hoffler, D., Narjes, H. H., Nehmiz, G. and Heinzel, G.: Pharmacokinetics of meloxicam in patients with end-stage renal failure on haemodialysis: a comparison with healthy volunteers. Eur J Clin Pharmacol, 51(3-4): 309-313, 1996. 6) Schmid, J.: Meloxicam: Pharmacokinetics and metabolic pattern after intravenous infusion and oral administration to health subjects. Drug Metab Dispos, 23(11): 1206, 1995.