Pharmacokinetics of oxaprozin in women receiving conjugated estrogen.

The kinetics of a single 1200 mg oral dose of oxaprozin, a nonsteroidal antiinflammatory agent of the propionic acid class, was studied in 22 healthy female volunteers aged 21 to 64 years. Eleven subjects had been taking a conjugated estrogen preparation for at least 3 months; the other 11 subjects served as control women who were not taking conjugated estrogens. Mean pharmacokinetic variables in control and conjugated estrogen groups were: volume of distribution, 15.1 vs 14.1 l; elimination half-life, 59.8 vs 54.2 h; clearance, 3.2 vs 3.1 ml/min; peak plasma concentration, 84.8 vs 90.7 micrograms/ml, respectively. None of the differences were significant. However, the time of peak concentration (8.9 vs 4.0 h) was significantly longer in the control group than in the conjugated estrogen group, respectively (p less than 0.05). Oxaprozin clearance, accomplished by a combination of oxidation and conjugation, is unimpaired by coadministration of conjugated estrogens.

Influence of age, gender, and obesity on salicylate kinetics following single doses of aspirin.

Salicylate kinetics following single, 650-mg intravenous and oral doses of aspirin were evaluated in humans in 2 studies. Complete conversion of aspirin to salicylate was assumed. The first study involved 25 young (25-40 years) and 21 elderly (66-89 years) healthy male and female volunteers. Mean salicylate clearance was lower in elderly females compared with that in young females; however, the difference between young men and elderly men was not significant. Salicylate free fraction in plasma increased significantly with age in men and women. After correction for free fraction, unbound mean clearance was reduced in elderly men compared with young men, and in elderly women compared with young women. Peak plasma salicylate concentrations after taking oral aspirin were not significantly influenced by age, and systemic availability of salicylate in all groups was complete. The second study compared 20 obese subjects (mean weight 113 kg) with 20 normal weight controls (mean weight 67 kg) matched for age, sex, height, and smoking habits. Small differences between obese and control groups were observed in total salicylate volume of distribution (Vd), unbound Vd, and mean clearance of total or unbound salicylate. Following normalization for total weight, however, values of total Vd and mean clearance were significantly smaller in obese subjects than in normal weight subjects. Rate and completeness of salicylate absorption were not influenced by obesity when aspirin was ingested, although peak levels were lower in obese subjects. If applied to multiple doses, the reduced unbound clearance of salicylate in the elderly would imply increased accumulation unless doses are appropriately adjusted downward. During long-term therapy, salicylate dosage for obese individuals should not be adjusted upward in proportion to total weight.

Temazepam clearance unaltered in cirrhosis.

The kinetics of a single oral dose of the benzodiazepine hypnotic temazepam was evaluated in nine patients with biopsy-proven cirrhosis and in seven healthy controls matched for age and sex. Peak serum temazepam concentrations were reached later in cirrhotics than in controls (2.9 versus 0.6 h after dosage; p less than 0.05), indicating slower temazepam absorption in patients with cirrhosis. Temazepam volume of distribution was smaller in cirrhotics compared to controls, and elimination half-life shorter (10.6 versus 14.6 h). However, these differences were not significant. There were no significant differences between cirrhotics and controls in clearance of total temazepam (1.03 versus 1.03 ml/min/kg), clearance of unbound temazepam (27 versus 31 ml/min/kg), or free fraction in serum (3.9 versus 3.5% unbound). In two cirrhotic patients who received 20 mg of temazepam daily for 8 days, the extent of accumulation was consistent with the dosage interval relative to the elimination half-life, and was similar to the accumulation profile in healthy volunteers. Thus the onset of temazepam hypnotic activity may be delayed in cirrhotic patients, but the rate of elimination and the extent of accumulation are not altered compared to healthy persons of similar age and sex.

Interaction of oxaprozin with acetaminophen, cimetidine, and ranitidine.

Twelve healthy male volunteers participated in a single-dose four-way crossover study to evaluate potential drug interactions with oxaprozin, a nonsteroidal antiinflammatory agent of the propionic class. The four modes of administration were: a. oxaprozin, 1200 mg alone; b. oxaprozin during concurrent acetaminophen, 500 mg 4 times daily; c. oxaprozin with cimetidine, 300 mg 4 times daily; d. oxaprozin with ranitidine, 150 mg every 12 hours. Acetaminophen, cimetidine, or ranitidine were begun 24 hours prior to oxaprozin dosage and continued for the 10-day duration of each trial. No significant differences existed among the four treatment conditions in peak plasma oxaprozin concentration (86 micrograms/ml), volume of distribution (0.23 l/kg), time of peak concentration (3.7 h after dosage), or elimination half-life (54 h). Oxaprozin oral clearance was significantly lower (by 20%) during both the cimetidine and ranitidine trials versus control (0.047 vs 0.047 vs 0.059 ml/min/kg), but clearance during acetaminophen was not significantly different from control. Thus acetaminophen, cimetidine or ranitidine has only a small influence on the pharmacokinetics of a single oral dose of oxaprozin. The reduction in oxaprozin clearance due to cimetidine or ranitidine is statistically significant but small in magnitude.

Interaction of ibuprofen with the H-2 receptor antagonists ranitidine and cimetidine.

The influences of cimetidine and ranitidine on single-dose ibuprofen kinetics were evaluated. Thirteen healthy subjects took a single, 600 mg oral dose of ibuprofen on three occasions: in the control state without drug coadministration; during concurrent dosing with cimetidine, 1.2 gm/day; and during concurrent dosing with ranitidine, 150 mg twice daily. Compared with the control state, cimetidine increased the peak serum ibuprofen concentration (64 vs. 56 micrograms/ml), but the value during ranitidine dosing (57 micrograms/ml) was indistinguishable from the control value. There were no significant differences between control, cimetidine, and ranitidine conditions in ibuprofen elimination t1/2 (2.1, 2.1, and 2.0 hours, respectively). Overall there was a significant difference among the control, cimetidine, and ranitidine conditions in ibuprofen oral clearance (52.8, 48.3, and 54.1 ml/min, respectively), but individual differences in cimetidine vs. control and between ranitidine vs. control were not statistically significant. The impairment of ibuprofen clearance by cimetidine is small, and ranitidine had no detectable effect on ibuprofen kinetics. These findings should be further validated during chronic dosing with ibuprofen.

Oxaprozin pharmacokinetics in the elderly.

A series of 42 healthy male and female volunteers aged 21 to 89 years received a single 1200 mg oral dose of oxaprozin. Kinetics were determined from multiple plasma oxaprozin concentrations measured by h.p.l.c. during 14 days after the dose. Peak plasma oxaprozin concentrations were reached between 3 and 6 h after dosage the majority of subjects, probably reflecting slow absorption from the gastrointestinal tract. Elimination also was slow with a mean half-life of 59 h (range 36 to 92 h). Owing in part to extensive protein binding (mean free fraction 0.0023%), oxaprozin distribution was limited, with apparent volume of distribution averaging 0.25 l/kg. Apparent volume of distribution declined with increasing age, probably reflecting the reduction in lean mass relative to total weight that occurs in the elderly. Total apparent oxaprozin clearance declined with age in men (r = -0.58, P less than 0.01), but was not significantly related to age in women (r = -0.25, NS). This is consistent with the previously described gender-specific reduction in hepatic oxidizing capacity association with increasing age. Thus oxaprozin is a slowly eliminated nonsteroidal anti-inflammatory agent that should be suitable for once daily or every other day administration.

Cimetidine disposition in obesity.

Cimetidine pharmacokinetics were studied in 13 otherwise healthy but obese volunteers, having a mean body weight of 113 kg and a mean percentage ideal body weight (IBW) of 179%. Sixteen healthy volunteers of normal body habitus (64 kg, 99% IBW) served as controls. All subjects had normal renal function and no laboratory or clinical evidence of hepatic or cardiac dysfunction. After administration of 200-300 mg of cimetidine by rapid intravenous injection, multiple plasma samples obtained over the next 24 h were analyzed for cimetidine concentration by high pressure liquid chromatography. Elimination half-life was not different between obese and control subjects (2.23 versus 2.08 h). Apparent volume of distribution was also similar between subject groups (120 versus 106), as was total metabolic clearance (616 versus 579 ml/min). Using percentage IBW as a measure of obesity, no relationship was found between percentage IBW and apparent volume of distribution (r = 0.29). Cimetidine similarly distributes into IBW in both obese and normal weight subjects, and there is minimal distribution of cimetidine into excess body weight over IBW. Furthermore, there is no difference in total metabolic clearance or half-life of cimetidine between obese and control subjects. Cimetidine dosage in clinical practice should therefore be calculated on the basis of IBW, which better reflects lean body mass, instead of total body weight, which reflects adipose tissue weight in addition to lean body mass.