Relationships between the concentrations of prostaglandins and the nonsteroidal antiinflammatory drugs indomethacin, diclofenac, and ibuprofen.
OBJECTIVE
To study the concentration-effect relationships of the nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin, diclofenac, and ibuprofen; to investigate whether standard doses of these drugs inhibit prostaglandin concentrations to a similar extent, determined by measuring the concentration of a surrogate marker of prostaglandin E 2 (PGE 2 ); and to determine the extent to which dose increases produce analogous increases in prostaglandin inhibition.


METHODS
Single-dose, randomized, crossover trial with a 1-week washout period.


METHODS
University biopharmaceutics and pharmacokinetics laboratory.


METHODS
Eight healthy adult volunteers younger than 35 years old.


METHODS
Subjects were administered two different standard doses of regular formulations (not enteric coated) of each NSAID on separate occasions.


RESULTS
Plasma samples were collected for determination of drug and 13,14-dihydro-15-keto-PGE 2 (PGEM; the surrogate marker of PGE 2 ) concentrations at regular intervals after administration of each NSAID dose. Statistically significant linear correlations were found between the percent reduction in PGEM concentration and the concentrations of diclofenac, indomethacin, and ibuprofen in plasma (R 2 = 0.992-0.999). The PGEM plasma concentrations correlated inversely with NSAID plasma concentrations, indicating maximum inhibition when the highest NSAID plasma concentrations were achieved. Statistically significant differences in the percent inhibition of PGEM concentrations were observed between the two doses for each NSAID (p<0.05), but not between subjects for each NSAID. Doubling the dose (100% increase) of diclofenac and indomethacin produced a 60-65% increase in maximum inhibition of PGEM concentrations, whereas a 50% increase in dose produced a 44% increase in the maximum effect of ibuprofen.


CONCLUSIONS
Prostaglandin inhibition, as measured by changes in PGEM concentrations, correlated significantly with NSAID concentrations in plasma and differed significantly between high and low NSAID doses. Measurement of PGEM plasma concentrations appears to be a promising marker for estimation of relative potency of NSAIDs.
Giagoudakis
George
G
Laboratory of Biopharmaceutics and Pharmacokinetics, School of Pharmacy, University of Athens, Athens, Greece.
Markantonis
Sophia L
SL
D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology; D002214:Capsules; D018592:Cross-Over Studies; D004008:Diclofenac / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology; D007213:Indomethacin / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D013607:Tablets; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002214:Capsules; D013607:Tablets; D004008:Diclofenac; C025087:15-keto-13,14-dihydroprostaglandin E2; D015232:Dinoprostone; D007052:Ibuprofen; D007213:Indomethacin