Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits the cyclooxygenase enzymes COX1 and COX2, preventing the formation of prostaglandins and leading to analgesic, antipyretic, and anti-inflammatory effects. It is rapidly absorbed orally and highly protein bound, undergoing extensive hepatic metabolism primarily by CYP2C9 and excreted in urine as metabolites. While generally safe, it can cause gastrointestinal adverse effects and interacts with other drugs like aspirin and warfarin by inhibiting platelet aggregation.

1. IBUPROFEN
-Priya Srivastava
14/IBT/033

2. Introduction
• Ibuprofen (IBU) is a traditional non-steroidal anti-
inflammatory drug (NSAID) widely used in the
treatment of mild to moderate pain and inflammation.
• Formula = C13H18O2
• T1/2 = 1.8 – 2 hours
• IBU inhibits the cyclooxygenase enzymes COX1 and
COX2 coded for by PTGS1 and PTGS2, preventing the
formation of various prostaglandins

4. • Ibuprofen has a wide therapeutic concentration range
for its analgesic, antipyretic, and anti-inflammatory
effects .
• The inhibition of COX inhibits the production of
prostaglandins and thromboxanes. This, in turn, leads to
the following three major effects:-
• Anti-inflammatory effect: modification of inflammatory
reactions via decrease in vasodilator prostaglandins.
• Analgesic effect: reduction of certain sorts of pain via
reduced sensitivity of nerves to certain inflammatory
mediators.

5. • Antipyretic effect: lowering of a raised temperature via
decrease in a mediator prostaglandin which is
responsible for elevating the hypothalamic temperature
control.

6. Uses:
• Relieve minor pain and inflammation, including
headache, muscular aches, toothache, fever, backache.
• It is used for the long-term treatment of rheumatoid
arthritis, spondylitis, and other chronic conditions.

7. Absorbtion:
• The absorption of ibuprofen is rapid and complete when
given orally.
• Prescribed doses of ibuprofen :
 adult: 200–800 mg every 6–8 h
 pediatric: 5–10 mg/kg every 6–8 h
• An intravenous formulation is also approved for use in
the USA.

8. • ibuprofen is administered as a racemic mixture
of R and S enantiomers, with S-ibuprofen being largely
responsible for its pharmacologic activity.
• R-ibuprofen undergoes inversion to the S enantiomer
through an acyl-CoA thioester by the enzyme α-
methylacyl-coenzyme A racemase

9. Distribution
• Ibuprofen binds extensively, in a concentration-
dependent manner, to plasma albumin. (200-400mg).
• At doses greater than 600mg there is an increase in the
unbound fraction of the drug, leading to an increased
clearance of ibuprofen.

10. • IBU exhibits a low apparent volume of distribution that
approximates plasma volume (~0.1–0.2 l/kg).
• but it is able to penetrate into the central nervous system
(CNS) and accumulate at peripheral sites where its
analgesic and anti-inflammatory effects are required.
• Ibuprofen is present in cerebrospinal fluid and in the
synovial fluid in the inflamed joints of arthritic patients.

11. Metabolism
• Metabolisation occurs mainly in liver and sometimes in
gut also.
• Ibuprofen is almost completely metabolized, with little to
no unchanged drug found in the urine.

12. • The primary metabolism of IBU is oxidative and involves
the cytochrome P450 enzymes.
• A number of other CYPs are capable of metabolism at
high concentrations of IBU: CYP3A4, CYP2C8,
CYP2C19, CYP2D6, CYP2E1, and CYP2B6 for 2-
hydroxylation and CYP2C19 for 3-hydroxylation.
• Metabolism of S-IBU takes place predominantly via
CYP2C9 whereas R-IBU is more via CYP2C8.
• The major primary metabolites found in urine are
carboxy IBU and hydroxy metabolites 2-OH IBU, , 3-OH
IBU; with 1-OH IBU a minor product .

13. • Secondary metabolism of IBU by glucuronidation occurs
via the UGTs (UDP-glucuronosyltransferases) including
UGT1A3, UGT1A9, UGT2B4, UGT2B7, and UGT2B17 ;
UGT1A10, which is predominantly expressed in the gut.
• CYP-derived hydroxy and carboxy metabolites are
metabolized to the corresponding acyl glucuronides.

14. • Although glucuronidation is generally considered a
detoxification pathway, acyl glucuronides are potentially
reactive metabolites.
• They can undergo intramolecular rearrangement and are
capable of binding covalently to macromolecules and
contributing to toxicity.

15. Excretion
• Urinary excretion of the two major metabolites, carboxy-
ibuprofen and 2-hydroxy-ibuprofen (and their
corresponding acyl glucuronides).
• CYP2C9 is the primary CYP isoform responsible for
ibuprofen clearance.

16. Transport
• Various classes of transporters interact with IBU:
 organic anion transporters in the kidney and GI tract
(hOAT family)
 hepatic organic anion transporters (hOATP family)
 multi-drug resistance protein family of transporters
(MRPs)
 the intestinal peptide transporter (SLC15A1).

17. • IBU is a weak acid and lipid soluble so it is feasible that it
may be able to cross membranes without the need for
specific transporters.
• The organic anion transporters SLC22A6 (hOAT1),
SLC22A7 (hOAT2), SLC22A8 (hOAT3) and SLC22A9
(hOAT4) are capable of uptake of IBU in vitro .
• IBU also interacts with SLC22A6 (hOAT1) and SLC22A8
(hOAT3) to inhibit methotrexate uptake.

18. • clearance of methotrexate becoming inhibited leading to
toxic plasma drug levels.
• IBU inhibits ABCC2 (MRP2) and ABCC4 (MRP4) and
reduce uptake of methotrexate.

19. Pharmacodynamics
• The main mechanism of action of ibuprofen is the non-
selective, reversible inhibition of the cyclooxygenase
enzymes COX-1 and COX-2.
• COX-1 and COX-2 catalyze the first committed step in
the synthesis of prostanoids – prostaglandin (PG) E2,
PGD2, PGF2α, PGI2 (also known as prostacyclin), and
thromboxane (Tx) A2

20. • Prostaglandins are found in inflammatory exudates and
can reproduce the cardinal signs of inflammation,
including pain and fever.
• They are generated from arachidonate by the action of
cyclooxygenase (COX) isoenzymes.

22. • IBU exerts other biologic effects that may contribute to its
anti-inflammatory action.
• During inflammation, immune cells, such as
macrophages, mast cells, eosinophils, and neutrophils,
robustly produce some molecules that contribute to
inflammatory processes:
 reactive oxygen species (e.g. superoxide anion, O2
•−,
 hydroxyl radical, HO•
 and reactive nitrogen species (e.g. nitric oxide, •NO,
ONOO−)
• IBU was reported to scavenge HO•, •NO, and ONOO− .

23. Advantages
• A wide therapeutic window, and the lack of prolonged
retention in specific body compartments make ibuprofen
a relatively safe drug.
• Have greater antipyretic and analgesic effects in both
children and adults compared with commonly used
doses of acetaminophen (adult: 500–1000 mg every 6–8
h; pediatric: 10–15 mg/kg every 4–6 h)

24. Disadvantages
• Rare cases of serious skin diseases, such as the
Stevens–Johnson syndrome and toxic epidermal
necrolysis, have been reported in patients with ibuprofen
use (rate of less than 1 per 1 million)
• IBU can cause serious gastrointestinal and possibly
cardiovascular adverse events, especially at high doses.
• However, the risk for cardiovascular events might
increase with prolonged exposure to ibuprofen (i.e.
greater than 1 year)

25. • a relatively short plasma half-life (t1/2, ~ 1–2 h),
necessitating frequent administration to maintain
therapeutic plasma concentrations.
• IBU-glucuronide can account for 4% of plasma drug in
the elderly due to decreased clearance and may also be
elevated in individuals with renal impairment.

26. Drug-Drug Interactions
• IBU exhibits pharmacodynamic interactions with a
variety of drugs.
• Ibuprofen antagonizes the cardioprotective effect of low-
dose aspirin (acetylsalicylic acid) through competition for
the NSAID binding site of COX-1 in platelets.
• Aspirin is used for antiplatelet therapy for secondary
prevention of myocardial infarction and stroke.
• Ibuprofen antagonistic effect on aspirin antiplatelet
action.

27. • ibuprofen has a transient antiplatelet effect for 1 h during
the 8 h dosing interval, which may increase bleeding risk
when administered with other anticoagulant or
antiplatelet agents because it reversibly inhibits COX-1
in platelets.
• Administration of warfarin with ibuprofen was reported to
prolong the bleeding time.

28. • In patients with a bipolar affective disorder, the
concomitant use of lithium with NSAIDs has been
reported to increase the serum lithium level and reduce
lithium clearance, thus causing acute lithium intoxication.
• This is due to inhibition of prostaglandin-mediated
excretion of lithium in the distal tubule.