Bromfenac disposition in patients with impaired kidney function.

OBJECTIVES: To compare the pharmacokinetics of bromfenac among normal subjects and renally compromised patients and patients with end-stage renal disease. METHODS: Bromfenac pharmacokinetics were examined after a single 50 mg oral dose in 18 subjects with normal kidney function, 12 subjects with decreased kidney function, and 10 dialysis-dependent subjects. Protein binding was assessed by equilibrium dialysis. RESULTS: Mean peak concentrations and areas under the concentration versus time curve ranged from 3.3 to 3.9 micrograms/ml and 5.1 to 6.9 micrograms.hr/ml, respectively. The mean unbound fraction in the subjects receiving dialysis (0.29%) was nearly twice that in the subjects with normal kidney function (0.17%) and in the subjects with impaired kidney function (0.16%), but no differences were detected in clearance, volume of distribution, or their free fraction-corrected counterparts. Bromfenac half-life nearly doubled in the impaired and dialysis groups but was shorter than the anticipated 8-hour dose interval. Eight subjects had a total of 11 study events; none were serious and all were self-limited. CONCLUSIONS: These findings suggest that no dosage adjustment is necessary in patients with impaired kidney function, but clinical monitoring appropriate for their individual condition is recommended.

Pharmacokinetic-pharmacodynamic relationships of bromfenac in mice and humans.

The relationship between pharmacodynamic effect and plasma concentrations of the analgesic bromfenac was assessed retrospectively. The drug was administered in single doses of 5, 10, 25, 50, or 100 mg to patients with oral surgery pain. Concentration-effect curves were generated by a semiparametric pharmacokinetic-pharmacodynamic procedure. The bromfenac EC50 (the effect site concentration giving 50% of the maximum effect) was estimated to be 0.36 microgram/ml in patients when all five dose groups were combined, and an Emax model was used for pharmacodynamic response. A similar EC50 value, 0.40 microgram/ml, was obtained when bromfenac was tested in a mouse pain model. On the basis of combined-dose data, effect site concentrations were predicted to be above the analgesic EC50 for approximately 7-8 hours after a 50-mg bromfenac dose was taken in the fasting state. Predictions based on a pharmacokinetic-pharmacodynamic modeling procedure were in reasonable agreement with the clinical observations.

Concomitant etodolac affects neither the unbound clearance nor the pharmacologic effect of warfarin.

Potential interactions between the nonsteroidal anti-inflammatory etodolac and the anticoagulant warfarin were studied in 18 healthy subjects by use of a randomized, three-period crossover design. Each treatment lasted 2 1/2 days and consisted of warfarin, etodolac, or both drugs. Prothrombin time was determined daily during each warfarin period to measure pharmacologic effect. Total serum concentration and unbound fraction of both drugs were determined over the dose interval after the last dose of the study drug(s). Concomitant etodolac did not affect the prothrombin time response or the unbound clearance of warfarin. During concomitant etodolac administration, the median peak concentration of total warfarin was significantly decreased by 19% (p = 0.005), median total clearance was significantly increased by 13% (p = 0.0123), and the unbound fraction tended to increase (median unbound fraction of warfarin, 1.245% with etodolac and 1.045% without etodolac; p = 0.0979; not statistically significant). These observations suggest a small displacement of warfarin from serum protein by etodolac or a metabolite of etodolac. No etodolac pharmacokinetic parameter was significantly affected by concomitant warfarin administration. Thus etodolac does not appear to alter the unbound clearance of warfarin or augment its pharmacologic effect. Nevertheless, it is prudent that clinical monitoring be done for individuals taking these two compounds concomitantly.

Accumulation and washout kinetics of valproic acid and its active metabolites.

There is growing evidence that the metabolites of valproic acid (VPA) may be pharmacologically active and could contribute to both the therapeutic and toxic effects of the drug. The accumulation and washout kinetics of VPA and its oxidative metabolites were, therefore, examined in five healthy volunteers. Valproic acid (250-mg capsules) was administered bid for 15 days. Blood samples were obtained periodically during the 15 days of drug administration and for seven days following termination of treatment. Urine was also collected over the final dosing interval. Steady-state serum concentrations of VPA were achieved within three to four days of treatment. The accumulation of all metabolites in serum lagged behind that of the parent compound, with the mono-desaturated metabolites accumulating more slowly than the hydroxylated species. Furthermore, the apparent washout half-life of each metabolite was longer than the elimination half-life of VPA. In general, the unsaturated metabolites were eliminated more slowly than the hydroxylated metabolites. The serum and urinary metabolite profiles of VPA observed in the healthy volunteers were comparable with those reported for epileptic patients. The differences in the disposition kinetics of VPA and of its potentially active metabolites may explain the previously observed dissociation between the pharmacokinetics and pharmacodynamics of the drug in epileptic patients.

Effects of route of administration and repetitive dosing on the disposition kinetics of di(2-ethylhexyl) phthalate and its mono-de-esterified metabolite in rats.

The disposition kinetics of the plasticizer di(2-ethylhexyl) phthalate (DEHP) and its biologically active metabolite mono(2-ethylhexyl) phthalate (MEHP) were studied in rats following single or multiple administration of DEHP by various routes. Following a single intraarterial (ia) injection, a large apparent volume of distribution (5390 ml/kg) and a high rate of clearance (21.5 ml/min/kg) were observed for DEHP. The systemic availability of DEHP was low following both single po (13.6%) and ip (5.2%) administration. A marked route-dependency in the formation of MEHP from DEHP was observed. The circulating concentrations of MEHP were substantially higher than those of DEHP (i.e., area under the blood concentration-time curve (AUC) ratio of approximately 7) after po administration, whereas concentrations of the mono-de-esterified metabolite were much lower relative to the parent diester concentration after ia or ip administration (i.e., AUC ratio less than 0.4). Pharmacokinetic calculations revealed that approximately 80% of a po dose of DEHP undergoes mono-de-esterification, as compared to only about 1% of the dose following either ia or ip administration. Hence, the low po systemic availability of DEHP may be largely attributed to presystemic hydrolysis of DEHP to MEHP in the gut, whereas slow and/or incomplete absorption is the likely cause of the poor bioavailability of DEHP after ip administration. No significant accumulation in the circulating concentrations of DEHP or derived MEHP were observed following 7 days of repetitive administration of DEHP. However, multiple ip injections resulted in an apparent decrease in the rate and/or extent of DEHP absorption from the peritoneal cavity, while no significant change in the po absorption of the diester was observed. The striking difference in the MEHP to DEHP AUC ratio between po and ip routes was still evident after multiple dosing. These data suggest that previously reported differences in the biologic effects of DEHP in rodents following different routes of administration may be due to route dependency in the mono-de-esterification of the diester.

The relationship between serum concentrations and central nervous system actions of metoprolol.

The relationship between serum levels of metoprolol, hydroxymetoprolol and changes in psychomotor function as measured by standard reaction time and flash fusion frequency was studied. Blinded subjects were given placebo or 150 mg dose of metoprolol and crossed over on the next study day. Flash fusion frequency, reaction time, and serial blood levels of metoprolol and hydroxymetoprolol were collected. Oral dosing of metoprolol produced no significant changes in reaction time. However, significant decreases in flash fusion frequency were observed from 2 to 6 hours after the dose. Changes in flash fusion frequency were related to levels of metoprolol. Flash fusion frequency changes lagged behind the time course of metoprolol concentrations. The nadir of variance in the metoprolol plus hydroxymetoprolol concentration-effect relationship occurred when potency of hydroxymetoprolol was assumed to be 0.3 of metoprolol. These data suggest that the central nervous system actions of metoprolol are related to metoprolol serum levels and occur at low metoprolol concentrations. However, CNS effects of metoprolol do not intensify at high concentrations. Further CNS activity of hydroxymetoprolol may explain the lag seen in the relationship between concentration and CNS effect.