Piroxicam pharmacokinetics: recent clinical results relating kinetics and plasma levels to age, sex, and adverse effects.

A large body of data is available regarding the relationship between demographic factors, particularly age, sex, and disease state, and the pharmacokinetics of piroxicam. Of additional interest is the relationship between piroxicam pharmacokinetics (particularly steady-state plasma levels) and adverse effects. Studies with piroxicam that are reviewed herein include studies on kinetics in renal impairment, single-dose studies, multiple-dose studies, and therapeutic drug monitoring studies. Although results were not always consistent, some studies suggested that plasma levels of piroxicam tend to be increased in elderly female patients. However, the increases were small and did not correlate with adverse events. These data suggest that there is no correlation between piroxicam plasma concentrations and adverse events.

Pharmacokinetics of piroxicam in man.

Piroxicam is a potent antiinflammatory agent currently in widespread use for the treatment of various inflammatory conditions of man. Following single oral doses of 10 to 100 mg, piroxicam is rapidly and fully absorbed, and eliminated with a mean plasma half life of about 45 hr. Mean peak concentrations are about 2 micrograms/ml after single 20 mg doses and about 6 micrograms/ml at steady state with 20 mg daily. Multiple peaking suggests enterohepatic recirculation of drug. In accord with expectations, steady state is achieved within 7 to 12 days with no appreciable accumulation thereafter. Due to the long plasma half life, once daily dosing provides continuous exposure to drug, with concentrations fluctuating less than twofold. Coadministration of aspirin reduces piroxicam levels by about 20 percent; antacids have no effect on piroxicam plasma concentrations.

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.

Sensitive assay for determination of hydroxyzine in plasma and its human pharmacokinetics.

An assay suitable for hydroxyzine determination in human plasma following therapeutic doses was developed. The method involves GLC and chemical-ionization mass spectrometry of the acetate derivatives of hydroxyzine and of a pentadeuterated analog internal standard. Following administration of 100-mg single oral doses to normal male volunteers, peak plasma concentrations of approximately 80 ng/ml were observed; the half-life of drug removal was approximately 3 hr.

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.

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.

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 benzquinamide in man.

Using a newly developed sensitive gas chromatograph-mass spectrometer assay for benzquinamide, pharmacokinetics have been determined in man following the administration of intramuscular, oral, and rectal suppository doses. Drug is absorbed most rapidly from the intramuscular dose and least rapidly from suppositories. The mean apparent elimination half-life is 1.0-1.6 hr from all formulations. Benzquinamide is 33-39% bioavailable from the capsule and suppository formulations, relative to the intramuscular formulation. A high correlation between capsule and suppository bioavailabilities suggests that first-pass metabolism may account for at least part of the incomplete availability.

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%.

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%.

Selected ion monitoring assay for meclizine in human plasma.

A method has been developed for the quantification of meclizine in human plasma using gas chromatography mass spectrometry. Pentadeuterated meclizine was synthesized and used as an internal standard. The method gave linear results over a concentration range of 5-200 ng ml-1 and was used to determine plasma levels of meclizine following administration to a male volunteer.

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.

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.

Interaction of sudoxicam and aspirin in animals and man.

In rats, both the plasma concentrations and the anti-inflammatory activity of sudoxicam are depressed by concurrent administration of aspirin, being similar to that reported for other nonsteroidal agents, whereas, in man and monkey, plasma concentrations of sudoxicam are not affected by concurrent administration of aspirin. In this respect sudoxicam differs from such other nonsteroidal anti-inflammatory agents as indomethacin and naproxen.

Metabolism of indanyl carbenicillin by dogs, rats, and humans.

Indanyl carbenicillin, an ester of carbenicillin with indanol, is absorbed in the intestine after oral administration and is subsequently hydrolyzed to release the parent antibiotic which can be measured in serum and urine. To study the metabolism of indanyl carbenicillin, labeled indanol was prepared by exchange with tritiated water and was used, with phenylmalonyl chloride and 6-aminopenicillanic acid, to prepare labeled indanyl carbenicillin. Labeled indanol and indanyl carbenicillin were orally administered to dogs and rats with good recovery of label in the urine. In the dog, indanol, whether administered as such or as indanyl carbenicillin, was excreted in the urine as the glucuronide and sulfate ester conjugates of indanol and as conjugates of two hydroxyindanones and two hydroxyindanols, as determined by combined gas chromatography-mass spectrometry. Rats, conversely, excreted only the conjugates of indanol, whether indanol or indanyl carbenicillin was administered. After oral administration of unlabeled indanyl carbenicillin to humans, conjugates of indanol were recovered in the urine in excellent yield, as determined by a gas chromatographic assay. None of the other indanol metabolites formed by the dog was observed in human urine.