Pharmacokinetics of bepridil and two of its metabolites in patients with end-stage renal disease.

The pharmacokinetics of bepridil and 2 of its major metabolites (McN-A-2600 and McN-6303) were studied in 6 patients with end-stage renal disease (ESRD) before and after hemodialysis. Patients underwent dialysis 1 day after a single oral 200-mg dose of bepridil hydrochloride; blood was sampled for up to 7 days. The mean (+/- SD) peak plasma concentration, time of peak concentration, and area under the plasma concentration-time curve (0-168 hours) for each agent were as follows: bepridil, 806 +/- 321 ng/mL, 2.6 +/- 1.6 hours, 4.87 +/- 1.21 micrograms.h/mL; McN-A-2600, 57 +/- 16 ng/mL, 4.2 +/- 2.0 hours, 0.53 +/- 0.29 microgram.h/mL; McN-6303, 284 +/- 120 ng/mL, 4.7 +/- 1.5 hours, 4.06 +/- 1.11 micrograms.h/mL. The bepridil area under the curve corrected for dose was similar to that in healthy volunteers, suggesting that plasma clearance was unaffected by severe renal impairment. None of the compounds were removed by dialysis, and no rebound in plasma concentrations was observed after the end of dialysis. The disposition of bepridil appears to be unchanged in patients with ESRD; and is unaffected by hemodialysis. Thus, no dosage adjustment will be required for ESRD patients and those receiving hemodialysis with cuprophane filters.

Determination of codeine in plasma by high-performance liquid chromatography.

An automated, sensitive, and selective reverse-phase high-performance liquid chromatographic assay has been developed to measure codeine in plasma. The analysis requires only 1 ml plasma and is accomplished by detection of the fluorescence of codeine following extraction and concentration. The method is simple and rapid, involving a one-step extraction of codeine from alkalinized (pH 10.0) plasma into an organic layer of hexane/dichloromethane, 2/1. The organic layer was evaporated under nitrogen and the residue reconstituted with the mobile phase. The samples were chromatographed on a reverse-phase C-18 column using a mobile phase of acetonitrile-phosphate buffer, 80/20 (pH 5.80). The codeine and internal standard, N-allylnorcodeine, peaks were detected using a fluorescence detector. The retention times were 8.6 min for the internal standard and 11.3 min for codeine. Standard curves were linear from 10 to 250 ng/ml. The assay was validated by direct comparison with a gas chromatographic procedure that employed nitrogen-phosphorus detection. The assay has been employed for the analysis of several codeine studies using human, dog, and rat plasma.

Zomepirac--aspirin interactions in man.

The pharmacokinetic interaction between zomepirac and aspirin was studied in 12 healthy males who received a single dose of 100 mg zomepirac sodium on days 1 and 5 and 975 mg aspirin every 6 hours on days 2 to 5. The results indicated that in the presence of salicylate, the peak concentration of zomepirac was depressed; peak time, AUC(0-24 hr), and clearance of total drug remained unchanged. Percentage unbound zomepirac was increased twofold. In the presence of zomepirac, the peak concentration and AUC of salicylate were increased and clearance decreased. The data suggest that zomepirac and salicylate compete with each other for the enzymes and/or cofactors involved in glucuronidation. This competition for metabolic clearance offsets the consequences of the zomepirac-salicylate interactions at the plasma protein binding sites. However, in light of increased unbound zomepirac as well as decreased clearance of unbound drug, concomitant therapy of zomepirac and aspirin is not advised.

Pharmacokinetics of chlorzoxazone in humans.

Twenty-three normal male subjects received 900 mg of acetaminophen and 750 mg of chlorzoxazone as an oral suspension. Analysis of plasma samples indicated a rapid absorption and rapid elimination of chlorzoxazone. Average values of the elimination half-life and plasma clearance were 1.12 +/- 0.48 hr and 148.0 +/- 39.9 ml/min, respectively. Analysis of urine samples showed that chlorzoxazone was eliminated from the body as the glucuronide conjugate of the intermediate metabolite 6-hydroxychlorzoxazone, to the extent of 74% of the dose. The plasma and the urinary excretion data were fitted to theoretical equations, and excellent fits were obtained using a five-parameter pharmacokinetic model.

Clinical pharmacology of tolmetin: comparisons in rheumatoid arthritis patients and normal volunteers.

The pharmacokinetics of tolmetin sodium were studied in five patients with rheumatoid arthritis (RA) and five normal volunteers to determine whether data derived from normals could be applied to RA patients. In addition, prostaglandin E (PGE) levels in synovial fluid were compared with tolmetin levels in serum and synovial fluid. Both groups received 400 mg tolmetin every 6 hours for seven days. During a 24-hour washout period after the dose of tolmetin (400 mg) on day 8, blood and urine samples were obtained from all study participants, and synovial fluid samples from the RA patients only. The patients continued into a second 24-hour drug-free period, after which they received a single 400-mg dose of tolmetin. Blood and urine samples were again collected. No clinically or statistically significant differences in tolmetin kinetics between normal volunteers and RA patients were found. A comparison of multiple-dose and single-dose results in the patient group showed an 11 per cent increase in the tolmetin serum concentration after multiple dosing. Total PGE levels in synovial fluid remained significantly depressed in the patient group for 24 hours after the 400-mg test dose of tolmetin on day 8. These findings suggest that tolmetin serum kinetics may not be an appropriate indicator of the duration of biologic activity of tolmetin.

Simultaneous determination of tolmetin and its metabolite in biological fluids by high-performance liquid chromatography.

A highly sensitive and selective high-performance liquid chromatographic assay has been developed for the separation and quantitation of tolmetin and its major metabolite in human biological fluids, viz. plasma, urine and synovial fluid. Analysis of plasma and synovial fluid required only 0.5 ml of the sample. The sample was washed with diethyl ether and extracted with diethyl ether-chloroform (2:1). The extracted compounds were injected onto a reversed-phase column (RP-2) and absorbance was measured at 313 nm. The standard curves in plasma were found to be linear for both tolmetin and the metabolite at concentrations from 0.04 to 10.0 microgram/ml. Urine samples (0.5 ml) were diluted (1:1) with methanol containing the internal standard and were directly injected onto the reversed-phase (RP-2) column. Standard curves of tolmetin and metabolite in urine were linear in the range 5-300 microgram/ml. Serum and synovial fluid concentrations of tolmetin and its metabolite in patients receiving multiple doses of tolmetin sodium were determined using the assay procedure.

Tolmetin kinetics and synovial fluid prostaglandin E levels in rheumatoid arthritis.

Tolmetin kinetics were determined in the plasma and synovial fluid of five rheumatoid arthritis patients after they had ingested tolmetin (400 mg every 6 hr) for 7 days. Tolmetin was rapidly absorbed, with average peak levels in plasma and synovial fluid occurring at 45 min and 2 hr. The drug concentration in synovial fluid was higher than that in plasma for prolonged periods, while the rates of elimination from both plasma and synovial fluid were similar. The average half-lives of tolmetin in plasma and synovial fluid were 6.77 +/- 1.47 hr and 6.90 +/- 2.3 hr. Total prostaglandin E levels in synovial fluid of these patients were suppressed for at least 24 hr after the last dose of tolmetin, suggesting that PGE synthesis continues to be suppressed even by the very low concentrations of tolmetin remaining after 24 hr.

Determination of theophylline and its metabolites by liquid chromatography.

A high pressure liquid chromatographic assay has been developed for the separation and quantitation of theophylline and its metabolites (1-methyl uric acid, 3-methyl xanthine, and 1,3-dimethyl uric acid), theobromine, and dyphylline in biological fluids, viz. human serum, urine, and saliva. The serum has been rendered protein-free by passage through a filter with a nominal molecular weight limit of 10,000. The filtrate is injected onto a reverse-phase column and the separation achieved by utilizing a polar mobile phase and dyphylline (dihydroxypropyl theophylline) as the internal standard. The results for two normal subjects are included to illustrate the applicability of the technique.