Prinomide tromethamine pharmacokinetics: mutually dependent saturable and competitive protein binding between prinomide and its own metabolite.

Abstract:

:Prinomide tromethamine, a nonsteroidal antiinflammatory drug, was orally administered at doses of 250, 500, and 1000 mg every 12 hr for 28 days to healthy male volunteers. The pharmacokinetic behavior of prinomide and its primary plasma metabolite displayed nonlinear characteristics, while those of free prinomide and its metabolite were dose proportional. The nonlinear pharmacokinetic behavior of total prinomide and p-hydroxy metabolite was found to be caused by both saturable and mutually dependent competitive Langmuir-type plasma protein binding between prinomide and its p-hydroxy metabolite. The extent of the protein interaction displayed at steady state was due to the extensive accumulation of the p-hydroxy metabolite. While ligand-protein interactions are known for xenobiotic competitors, the characteristic behavior of prinomide is the first known example to be reported for a competitive protein interaction between a xenobiotic and its own in vivo generated metabolite. The findings of this study may have implications regarding the disposition of other extensively bound nonsteroidal antiinflammatory drugs with long-lived metabolites.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Kochak GM,Pai S,Iannucci R,Honc F,Kachmar D,Perrino P,Egger H

doi

10.1023/a:1018916811904

subject

Has Abstract

pub_date

1993-01-01 00:00:00

pages

49-55

issue

1

eissn

0724-8741

issn

1573-904X

journal_volume

10

pub_type

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