Clinical Pharmacokinetics of Ibuprofen: The First 30 Years

DRUG DISPOSITION Clin Pharmacokinet 1998 Feb; 34 (2): 101-154
0312-5963/98/0002-0101/$27.00/0
© Adis International Limited. All rights reserved.
Clinical Pharmacokinetics of Ibuprofen

The First 30 Years
Neal M. Davies
Faculty of Medicine, Department of Pharmacology and Therapeutics, University of Calgary,
Calgary, Alberta, Canada
Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
1. Analytical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
2. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
2.1 Oral Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
2.2 Topical Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
2.3 Inversion and Stereoisomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
2.4 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
2.5 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
2.6 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
3. Implications of Pharmacokinetic Properties for Therapeutic Use . . . . . . . . . . . . . . . . . . . 135
3.1 Rationale for Development of Stereochemically Pure S-Ibuprofen . . . . . . . . . . . . . . . 135
3.2 Dose and Therapeutic Range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
3.3 Disease and the Pharmacokinetics of Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . 139
3.4 Influence of Age on the Pharmacokinetics of Ibuprofen . . . . . . . . . . . . . . . . . . . . . 141
4. Pharmacokinetic Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
4.1 Effect of Other Drugs on the Pharmacokinetics of Ibuprofen . . . . . . . . . . . . . . . . . . . 142
4.2 Effect of Ibuprofen on the Pharmacokinetics of Other Drugs . . . . . . . . . . . . . . . . . . . 144
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Summary Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2

arylpropionic acid (2-APA) class. A common structural feature of 2-APA NSAIDs
is a sp3-hybridised tetrahedral chiral carbon atom within the propionic acid side
chain moiety with the S-(+)-enantiomer possessing most of the beneficial anti-
inflammatory activity. Ibuprofen demonstrates marked stereoselectivity in its
pharmacokinetics. Substantial unidirectional inversion of the R-(–) to the S-(+)
enantiomer occurs and thus, data generated using nonstereospecific assays may
not be extrapolated to explain the disposition of the individual enantiomers.
The absorption of ibuprofen is rapid and complete when given orally. The
area under the plasma concentration-time curve (AUC) of ibuprofen is dose-
dependent. Ibuprofen binds extensively, in a concentration-dependent manner, to
plasma albumin. At doses greater than 600mg there is an increase in the unbound
fraction of the drug, leading to an increased clearance of ibuprofen and a reduced
AUC of the total drug. Substantial concentrations of ibuprofen are attained in
synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory
drugs.
102 Davies
Ibuprofen is eliminated following biotransformation to glucuronide conjugate

metabolites that are excreted in urine, with little of the drug being eliminated
unchanged. The excretion of conjugates may be tied to renal function and the
accumulation of conjugates occurs in end-stage renal disease. Hepatic disease
and cystic fibrosis can alter the disposition kinetics of ibuprofen. Ibuprofen is not
excreted in substantial concentrations into breast milk.
Significant drug interactions have been demonstrated for aspirin (acetylsali-
cylic acid), cholestyramine and methotrexate. A relationship between ibuprofen
plasma concentrations and analgesic and antipyretic effects has been elucidated.
Ibuprofen, (±)-(R,S)-2-(4-isobutylphenyl)-pro- currently used chiral NSAIDs, its anti-inflammatory

pionic acid (fig. 1), is a chiral 2-arylpropionic acid activity has been attributed almost entirely to the
(2-APA) derivative nonsteroidal anti-inflamma- S-(+)-enantiomer, and stereoselective pharmacoki-
tory drug (NSAID). Ibuprofen was developed as an netics have been extensively studied.[4] General re-
antirheumatic drug in the 1960s[1] and has been view articles are available which deals with the
widely used as a prescription drug in Great Britain pharmacological and therapeutic uses of ibuprofen,
since 1967 and since 1974 in the US. Ibuprofen however, the issue of chirality has been ignored.[7,8]
became available without a prescription in the US In this article the first 30 years of the clinical phar-
and the UK in 1984. macokinetics of ibuprofen and its enantiomers are
Ibuprofen is a potent inhibitor of prostaglandin updated and reviewed. Unless otherwise stated, all
synthesis with the S-(+)-enantiomer possessing the doses throughout the review refer to the adminis-
majority of pharmacological activity. S-(+)- tration of the racemate.
ibuprofen has been reported to be about 160 times
more potent than R-(–)-ibuprofen in inhibiting 1. Analytical Methods
prostaglandin synthesis in vitro.[2-4] Racemic Several analytical methods are available for
ibuprofen has half the potency of S-(+)-ibuprofen quantitative analysis of ibuprofen in biological
in inhibiting platelet aggregation and thromboxane specimens (table I). The earlier methods employed
formation, while R-(–)-ibuprofen was about 2 or- thin-layer spectrophotometric, colorimetric, paper
ders of magnitude less active.[5] Ex vivo studies of chromatography, differential pulse polagraphy,
thromboxane generation in clotting blood also gas-liquid chromatography or direct liquid intro-
found S-(+)-ibuprofen to be twice as potent as the duction mass spectrometry (MS).[16-21,33,37,40,78,79]
racemate.[6] However, due to greater precision and facile sam-
In the treatment of rheumatoid arthritis, osteo- ple preparation, these methods have largely been
arthritis, ankylosing spondylitis, acute gouty ar- replaced by high performance liquid chromatogra-
thritis and dysmenorrhoea, therapeutic doses of phy (HPLC) [see table I], gas chromatography
ibuprofen have proven to be equiefficacious as (GC),[22,25,26,45,80] gas chromatography-mass spec-
compared with other commonly used NSAIDs. trometry (GC-MS)[52,70,72,74,77,81,90,97,105,106] and a
Gastrointestinal (GI) complications are the most recent report describes the use of high performance
common adverse effect, but renal dysfunction may thin-layer chromatography.[107]
also occur.[7,8] The earlier assays of ibuprofen overlooked the
Excellent review articles describing the clinical fact that it is administered as the racemate. How-
pharmacokinetics and pharmacodynamics of sev- ever, since 1975 GC and HPLC techniques have
eral other chiral NSAIDs are available.[9-15] Similar been available which allow for the separation and
to other NSAIDs, ibuprofen exhibits enantio- quantification of the 2 enantiomers. These methods
selectivity in action and disposition. As with all of stereospecific analysis of ibuprofen have been
© Adis International Limited. All rights reserved. Clin Pharmacokinet 1998 Feb; 34 (2)

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DRUG DISPOSITION Clin Pharmacokinet 1998 Feb; 34 (2): 101-154

© Adis International Limited. All rights reserved.

Clinical Pharmacokinetics of Ibuprofen

Summary Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2

Ibuprofen is eliminated following biotransformation to glucuronide conjugate

Ibuprofen, (±)-(R,S)-2-(4-isobutylphenyl)-pro- currently used chiral NSAIDs, its anti-inflammatory

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