Stereoselective pharmacokinetics and inversion of (R)- ketoprofen in healthy volunteers.

The pharmacokinetics of ketoprofen enantiomers were evaluated after 25-, 50-, and 100-mg doses of (R)- ketoprofen and 100 mg of racemic ketoprofen in 25 healthy volunteers (12 male and 13 female). The fractional inversion (Finv) of (R)- ketoprofen was 8.9 +/- 3.3% using plasma data and 10.0 +/- 2.2% using urine data. There were small (< 5%) but significant differences between the enantiomers for areas under the plasma concentration-time curve (AUC) after the racemic dose (P < 0.005). Half-lives were 130-144 minutes for (R)- ketoprofen and 132-209 minutes for (S)- ketoprofen. Dose proportionality in AUC and maximum plasma concentration (Cmax) values was noted for both enantiomers. A total of 69% of the dose was recovered in the urine as (R)- and (S)- ketoprofen and conjugates. The elimination rate constant of (R)- ketoprofen was significantly different (P < 0.05) between men and women. Exposure to cyclooxygenase inhibiting (S)- ketoprofen was approximately 10% of the dose after the administration of pure (R)- ketoprofen and was independent of gender.

Furosemide pharmacokinetics and pharmacodynamics in renal transplantation.

Furosemide was administered intravenously to four patients who had undergone renal transplantation in the past and four creatinine clearance--matched control subjects. Both patients who had undergone renal transplant and control subjects displayed similar pharmacokinetic and pharmacodynamic behavior, as assessed by drug delivery to the urine and sodium excretion, respectively. Despite similar degrees of natriuresis, patients who had undergone renal transplantation demonstrated a clear defect in urine potassium excretion. This defect in potassium excretion was not related to altered responsiveness of the renin-angiotensin-aldosterone axis because plasma renin activity increased in a normal fashion after furosemide in both control and transplant subjects. Although the plasma aldosterone response to increases in plasma renin activity was sluggish in patients undergoing renal transplantation, normal increases in plasma aldosterone levels were achieved in both groups, suggesting that there may be an intrinsic defect in distal tubular potassium secretion that can be unmasked by furosemide.

Tiotidine, a new long-acting histamine H2-receptor antagonist: comparison with cimetidine.

The effects of tiotidine, a new histamine H2-receptor antagonist, and cimetidine on food-stimulated gastric acid secretion were evaluated in duodenal ulcer patients. Homogenized steak meals were infused immediately after, 1 h after, 5 h after, and 10 h after an oral dose of medication, and food-stimulated acid secretion was measured by in vivo intragastric titration. Tiotidine and cimetidine had a similar onset of action; however, tiotidine was more potent and had a longer duration of effect. Increased potency was demonstrated by the fact that from 1 to 2 h after medication 150 mg tiotidine inhibited acid secretion to approximately the same extent as did 300 mg cimetidine, and by the fact that for a given percent inhibition of acid secretion, plasma tiotidine concentration was eight to nine times lower than plasma cimetidine concentration. Longer duration of effect was demonstrated by the fact that from 5 to 7 h after medication, acid secretion was inhibited by 80% and 97% with 150 and 300 mg tiotidine, respectively, whereas 300 mg cimetidine inhibited acid secretion by only 22%. Also, 10-12 h after medication, 150 and 300 mg tiotidine inhibited acid secretion by 22% and 53%, respectively, while 300 mg cimetidine had no inhibitory effect. The long duration of effect was due in part to increased potency and in part to a plateau in plasma concentration of tiotidine, which was maintained from 2 to 6 h after medication. Neither tiotidine nor cimetidine had a significant effect on food-stimulated gastrin release or gastric emptying of a nonabsorbable marker.

Indomethacin and the response to bumetanide.

Pretreatment of 8 normal subjects with 100 mg indomethacin decreased the response to bumetanide; cumulative 4-hr excretion of sodium due to 1.0 mg of bumetanide was reduced from 276 +/- 22.9 to 202 +/- 20.9 mEq (p less than 0.003). Effects on volume and Cl paralleled those on Na while K excretion was not affected. When response was analyzed as increment in fractional excretion over basal solute excretion determined from separate control studies, indomethacin decreased response, an effect differing from that of indomethacin on the response to furosemide. The importance and mechanism of the difference in the effect of indomethacin on bumetanide and furosemide is not known.

Effects in normal subjects of long-term administration of azosemide.

Azosemide is a new loop diuretic which has been shown to affect solute transport proximal to the diluting segment. We assessed the effects of chronic administration of azosemide in normal subjects on low and normal salt diets. In both, there was compensatory renin release and aldosterone secretion, but the subjects on the low sodium diet developed striking hyperuricemia and metabolic alkalosis and were symptomatic, whereas those on the normal diet compensated to the extent that there were only minor changes.