No abstract

It has been shown that the analgesic and cyclooxygenase inhibitor activity of ketorolac tromethamine (KT), which is marketed as the racemic mixture of (-)S and (+)R enantiomers, resides primarily with (-)S ketorolac and that the ulcerogenic activity of this agent also resides in (-)S ketorolac. Resolution of individual enantiomers for analysis in plasma samples has been accomplished by two methods: derivatization to form diastereomers that are separated by HPLC, or direct HPLC using a chiral phase column. When mice and rats were given oral solutions of (-)S and (+) KT, it was found that the kinetics and interconversion of the enantiomers were species and dose dependent. Interconversion was higher in mice than in rats; when (-)S KT was administered, 71% of the area under the concentration-time curve (AUC) was due to (+)R ketorolac in mice, compared with 12% in rats. More interconversion was observed at higher doses; the percent of AUC due to (-)S ketorolac when (+)R KT was administered increased from 12% to 25% in mice and from 2% to 8% in rats. In general, more interconversion occurred from (-)S to (+)R ketorolac in the animal studies. Human subjects were given single oral solution doses of racemic KT (30 mg), (-)S KT (15 mg), and (+)R KT (15 mg). The plasma concentrations of (-)S ketorolac were lower than (+)R ketorolac at all sample times after racemic KT (22% of the AUC was due to (-)S ketorolac). When (+)R KT was administered, (-)S ketorolac was not detectable and interconversion was essentially 0%. When (-)S KT was administered, significant levels of (+)R ketorolac were detectable and interconversion was 6.5%. After all doses, plasma half-life was shorter and clearance greater for (-)S ketorolac than for (+)R ketorolac. Thus, in humans very little or no interconversion of (+)R to (-)S was observed, and interconversion of (-)S to (+)R was minimal (6.5%). These data demonstrate that the kinetics and interconversion of the enantiomers of ketorolac is different in animals and humans as well as from most other NSAIDs. This may be due to more rapid excretion or metabolism of (-)S ketorolac and a different mechanism of interconversion.

No abstract

Flunisolide (6 alpha-fluoro-11 beta,16 alpha,17 alpha,21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetonide) is a potent corticoid used clinically in topical formulations. Three men were given single 2-mg intravenous and oral doses of 14C-labeled flunisolide and plasma and urine concentrations of flunisolide and a major metabolite, 6 beta,11 beta,16 alpha,17 alpha,21-penta-hydroxypregna-1,4-diene-3,20-dione 16,17-acetonide (6 beta-OH metabolite) were determined. Oral flunisolide was metabolized rapidly and extensively to the 6 beta-OH metabolite and to conjugates; comparison in the intravenous dose kinetics suggested significant first-pass metabolism. In a separate study in 12 normal subjects, flunisolide in plasma was quantitated by radioimmunoassay (RIA); average systemic availability was 20%. The apparent volume of distribution (Vd beta) of flunisolide was large and systemic clearance and apparent oral clearance values were high. The 6 beta-OH metabolite had corticoid activities no more than 3 times that of hydrocortisone in rats as measured by thymolytic, anti-inflammatory, and adrenal-suppressive assays, whereas flunisolide had 180 to 550 times the activity of hydrocortisone. These data offer a metabolic explanation for the clinical observation that flunisolide can be administered intranasally and by inhalation in therapeutically effective doses without causing significant reduction in adrenal function.

In earlier safety studies, naproxen, 600 mg three times daily, was administered to healthy subject without significant adverse effects. Another study demonstrated that single doses of 500 to 900 mg resulted in accelerated renal clearance and a nonlinear naproxen plasma level response after the higher doses. Our report describes the pharmacokinetics of naproxen when administered in single doses of 1, 2, 3, or 4 gm (up to eight times the clinically effective dose in rheumatoid arthritis) to healthy subjects. An increase in urinary excretion rate and continuation of the previously documented nonlinear plasma level response were observed. There were no signs that capacity to conjugate or to excrete the drug was exceeded. There were no adverse effects.

The plasma level curves of oral doses of naproxen ranging from 125 to 900 mg were studied in normal sub;ects. Areas under plasma concentration vs time curves increased linearly with dose incmments up to 500 mg twice a day, but larger doses resulted in a plateau effect. Experiments with tritium‐labeled naproxen showed that there was no difference in the fraction of drug excreted in the stools whether the dose was 250 or 900 mg, eliminating incomplete absorption as a factor. Accelerated renal clearance at high doses because of disproportionate increases in the amount of unbound drug appeared to be the most likely explanation for the plateau effect.

Probenecid induced major alterations in the half-life. renal clearance, and metabolism of naproxen. In 6 healthy subjects who received 500-mg single oral doses of naproxen alone and (following two days of probenecid loading) with 500 mg of probenecid 4 times a day, there was an increase in naproxen plasma half-life from the normal 14 to 37 hr. Twenty-jour hour naproxen plasma levels were doubled by probenecid. but the rate and extent of absorption were not affected. In an 8-day chronic administration experiment (250 mg twice daily). naproxen steady-state plasma levels measured before the morning dose were increased 50% by coadministration of 500 mg probenecid twice daily. The major probenecid effects on naproxen metabolism were a 66% reduction of the naproxen conjugates excreted in the urine and an increase in urinary 6-0-desmethyl naproxen. The renal clearance of unchanged naproxen was markedly depressed. We conclude that probenecid retards naproxen plasma clearance by inhibiting naproxen glucuronide formation and renal clearance of naproxen. The renal clearance effect is the result of the blocking of tubular secretion of organic anions by probenecid. Inhibition of conjugate formation by probenecid may be the result of successful competition for conjugative processes since a large percentage of both drugs are cleared from the plasma by conjugation. Because of this interaction, patients who receive naproxen and probenecid in combination will have higher steady-state plasma levels of naproxen and form more of the 6-0-desmethyl metabolite than when probenecid is not used.

Scand J Rlieumaiology, Suppl2 Scand J Rheumatol Downloaded from informahealthcare.com by McMaster University on 12/04/14 For personal use only. 1.920.7 0.1020.04 Scand J Rheumatol Downloaded from informahealthcare.com by McMaster University on 12/04/14 For personal use only. Human 94 1 Scand J Rheurnatology, Suppl2 Scand J Rheumatol Downloaded from informahealthcare.com by McMaster University on 12/04/14For personal use only.