Kinetics of polythiazide.

An assay for polythiazide, sufficiently sensitive to measure plasma concentrations of this high-potency diuretic agent, has been developed. The assay is based on acid hydrolysis to trifluoroethylthioacetaldehyde and electron-capture gas chromatography. Sensitivity down to 0.2 ng/ml was achieved. In a study in normal human subjects receiving single 1-mg oral doses of polythiazide, the mean plasma half-lives for absorption and elimination were 1.2 and 25.7 hr, respectively. The latter is consistent with the extended duration of action of polythiazide. Approximately 25% of the drug was excreted unchanged in the urine.

Prazosin kinetics and effectiveness in renal failure.

Single and repeated doses of prazosin were given to 17 hypertensive patients, 5 with normal renal function and 12 with impaired renal function. Blood for prazosin assay was drawn after a 1-mg single dose and after patients reached steady-state levels with their long-term maintenance dose. As blood was drawn blood pressure was recorded. Prazosin absorption was not altered in patients with impaired renal function, and there is no cumulation of the drug when given repeatedly to patients with impaired renal function. Elimination kinetics were virtually identical regardless of degree of renal function. Effect on blood pressure was significantly better at the dosage range of 3 to 8 mg/day than at higher doses of 9 to 20 mg/day. There does not appear to be a direct relationship between the peak plasma prazosin level and the nadir of antihypertensive response. This would seem to indicate that the drug leaves the plasma and goes to the vascular smooth muscle receptor site of action. There appears to be no impairment in prazosin elimination in patients with impaired renal function, and its effectiveness (with diuretic or dialysis) is optimum at 3 to 8 mg/day.

Effects of doxazosin on atherosclerosis in cholesterol-fed rabbits.

Doxazosin was administered to rabbits fed diets enriched in cholesterol and peanut oil for 7.5 or 12 weeks, in 2 separate experiments. Doxazosin suppressed the accumulation of cholesterol and formation of atherosclerotic plaques in the aortas of treated rabbits and prevented a diet-induced increase in aortic collagen and wall mass. Doxazosin was more effective in the thoracic and abdominal segments of the aorta than in the aortic arch. Pharmacokinetic analysis indicated that treated rabbits were exposed to concentrations of doxazosin, integrated over 24 h, which were consistent with the therapeutic range of doxazosin measured in patients treated for hypertension. Doxazosin did not alter serum levels of cholesterol or triglycerides, nor were there any consistent effects on glucose, free fatty acid or ketone levels. Hypotheses of the mechanism of action of doxazosin are discussed, including the possible involvement of alpha 1-adrenergic receptors in recruitment of smooth muscle cells by subintimal macrophages and nonadrenergic mechanisms of inhibition of lipid infiltration.

Piroxicam pharmacokinetics in man: aspirin and antacid interaction studies.

Pharmacokinetic studies with piroxicam, a nonsteroidal antiinflammatory agent, have been carried out following the administration of single and multiple oral doses. A plasma half-life of approximately 45 hours is observed, permitting the use of single daily doses in therapy. Enterohepatic recirculation of drug is suggested by the presence of multiple peaks in plasma concentration curves. Piroxicam is highly bound to serum proteins. The absorption and disposition of piroxicam are unaffected by the concomitant administration of aspirin and antiacids. Salicylate plasma levels are similarly unaffected by piroxicam administration.

Pharmacokinetics of prazosin in man.

Prazosin was administered orally to 24 normotensive human subjects in the form of capsules or as a solution. Plasma concentrations indicate that drug is almost completely bioavailable from the capsules, although levels peak more slowly than from drug in solution. Drug leaves plasma with a half-life of approximately 2.3 hours. Examination of data from each subject on repeated dosing indicates considerable intrasubject consistency in pharmacokinetic response despite intersubject variability. The absence of the pharmacologically active metabolites in plasma suggests that the hypotensive response derives from drug only. Prazosin is bound to human plasma proteins to the extent of 97%.

Analysis of prazosin in plasma by a sensitive high-performance liquid chromatographic-fluorescence method.

A specific high-performance liquid chromatographic-fluorescence method for the quantitative analysis of prazosin in plasma at concentrations down to 0.2 ng/ml is described. The method involves the coextraction of drug and an internal standard from alkalinized plasma followed by a simple purification step prior to evaporation and high-performance liquid chromatographic-fluorescence analysis. The method is sufficiently sensitive to allow pharmacokinetic analyses of 1-mg doses through five half-lives, with a relative standard deviation of 12%.

Liquid chromatographic analysis of doxazosin in human serum with manual and robotic sample preparation.

A specific method for the determination of the antihypertensive drug doxazosin in human serum is described. The method utilizes the related drug prazosin as an internal standard and is based on a simple extraction scheme followed by analysis by reversed-phase ion suppression high-performance liquid chromatography (HPLC) on an alumina-based column with fluorescence detection. The method is completely automated with a flexible robotic system for the analysis of drugs in biological fluids. The robotic automation of the method allows a 20% increase in the sample throughput and the savings of about 7 man-hours a day. Both the manual and robotic procedures yield precise quantitative results over the therapeutically relevant concentration range of 0.5 to 20 ng/mL of serum.

Metabolism of sudoxicam by the rat, dog, and monkey.

Sudoxicam, N-(2-thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1, 1-dioxide, was prepared in radiolabeled form and administered to rats, dogs, and monkeys. Urine contained approximately 60, 25, and 49% of the label given to rats, dogs, and monkeys, respectively; the remainder was cleared via feces. In addition to some unchanged drug, urine from all species examined contained two major metabolites. These were identified from their mass spectra as the thiohydantoic acid and thiourea resulting from scission of the thiazole ring of sudoxicam.

Metabolism of piroxicam by laboratory animals.

Piroxicam, a potent new nonsteroidal antiinflammatory agent, was radiolabeled in a biologically stable position by tritium exchange and administered at doses of 20 mg/kg to the rat, dog, and rhesus monkey. Metabolites were isolated from excreta by chromatographic methods and identified by their mass spectra and by comparison with authentic samples. Piroxicam is metabolized by cyclodehydration, by hydroxylation on the pyridyl moiety, and by a sequence of reactions involving amide hydrolysis, decarboxylation, ring contraction, and N-demethylation. In the rat, piroxicam is also metabolized by hydroxylation in two positions on the benzothiazine nucleus.

The analgetic properties of piroxicam in animals and correlation with experimentally determined plasma levels.

In animal antinociceptive tests responsive to non-steroidal anti-inflammatory drugs (NSAID), piroxicam is an extremely potent and effective analgetic at doses of 1--2 mg/kg p.o. In mice the plasma half-life and duration of analgetic action is short (t 1/2 = 1.7 h), unlike man, wherein piroxicam exhibits an exceptionally long duration of action (half-life 40--45 h). An excellent correlation is observed between plasma levels and analgetic activity in the writhing test in mice suggesting that piroxicam will exhibit potent and long-lasting analgetic activity in man.

Protein binding properties of prazosin.

The serum protein binding proerties of prazosin were determined by the equilibrium dialysis technique, using radiolabeled drug of high specific activity. At concentrations typically found in human therapy, prazosin is bound to serum proteins to the extent of approximately 92 percent. This value is not altered in the presence of several other drugs frequently diminished in conjunction with prazosin.

The metabolic fate of prazosin.

1. [2-14C]Prazosin is rapidly distributed into tissues of the dog including heart, lung and vascular tissues. 2. Urinary excretion by rats and dogs is low, biliary secretion being the major route of elimination. 3. Biotransformation of prazosin in the rat and dog occurs primarily by 6- or 7-O-dealkylation and subsequent glucuronide formation, and to a lesser extent via N-dealkylation. 4. Preliminary metabolic studies in man indicate a pattern of metabolites similar to that observed in dogs and rats.

Ampiroxicam, an anti-inflammatory agent which is a prodrug of piroxicam.

Ampiroxicam is a nonacidic ether carbonate prodrug of piroxicam. Our results demonstrate that, in contrast to piroxicam, ampiroxicam does not possess detectable prostaglandin synthesis inhibitory activity in vitro. Ampiroxicam, however, has similar in vivo potency to piroxicam in suppressing paw swelling in rat adjuvant arthritis. In an acute model of paw inflammation in rats, ampiroxicam is less potent than piroxicam itself: the ED50's of ampiroxicam are 9- and 3.5-fold higher than those of piroxicam following a single or multiple (5) daily oral doses, respectively. Using the phenylbenzoquinone stretching test as a method of evaluating acute analgetic activity, the ED50 for ampiroxicam is about 3-fold higher than that of piroxicam. These tests of activity share the property of being partially prostaglandin-dependent. Ampiroxicam itself is not observed in plasma after oral dosing to man, nor in the rat, dog, and monkey as reported here. Bioavailability studies show that conversion to piroxicam is about 100%, 90%, 70%, and 50% in these four species, respectively. These results indicate that ampiroxicam's anti-inflammatory activity is produced in vivo by conversion to piroxicam and support its credentials as an efficacious prodrug of piroxicam.

Disposition of ampiroxicam, a prodrug of piroxicam, in man.

1. Ampiroxicam, a prodrug of the effective anti-inflammatory agent piroxicam, was completely converted to piroxicam after oral administration to man. 2. At clinical doses there was no detectable portal or systemic exposure of man to ampiroxicam, indicating that conversion to piroxicam was complete during the absorption process. 3. The pharmacokinetics of piroxicam from ampiroxicam were essentially the same as those after piroxicam itself except that Cmax was slightly lower and tmax was slightly longer after administration of ampiroxicam.

Prazosin, pharmacokinetics and concentration effect.

The pharmacokinetics and effects of prazosin have been studied after intravenous and oral dosing (1 mg) to 6 normal male volunteers. The mean terminal (beta) half-life was 2.9 h after intravenous and oral routes. Oral bioavailability was 56.9%. The effects of prazosin on blood pressure were more pronounced after intravenous than oral administration, and the hypotensive effect greater on erect blood pressure. There was a significant correlation (P less than 0.02) between the fall in blood pressure and the plasma drug concentration after intravenous prazosin.