Source: Health Products and Food Branch (CA) Revision Year: 2020
Ibuprofen is a member of the class of agents commonly known as non-steroidal anti- inflammatory drugs (NSAID). Like all NSAIDs, ibuprofen is an analgesic, antipyretic, and anti- inflammatory medication (14).
It is generally accepted that the basic mechanism of pharmacological action of ibuprofen, and other NSAIDs, is the inhibition of prostaglandin synthesis (15, 16).
Nonselective NSAIDs (such as ibuprofen) and ASA act by inhibiting systemic (peripheral and central) prostaglandin G/H synthase isoenzymes, also known as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). These isoenzymes are responsible for the conversion of arachidonic acid to various tissue specific prostaglandins and thromboxanes (17,15). COX-1 is constitutively expressed in all tissues and is responsible for generating prostaglandins that maintain organ function, protect the integrity of the gastric mucosa and generate platelet-derived thromboxane responsible for platelet aggregation and vasoconstriction (18). During the inflammatory process COX-2 is induced, generating prostaglandins that mediate pain and inflammation (19). COX-2 is also present constitutively in the kidneys and vascular endothelium (15). Reported adverse experiences with ASA and other NSAIDs can be understood on the basis of this mechanism of action.
Consistent with the NSAID classification, ibuprofen exhibits anti-inflammatory activity at higher dosage ranges (20). At lower adult single doses relevant to a nonprescription dosage (200 mg to 400 mg) ibuprofen relieves pain of mild to moderate intensity (21, 22, 23, 24, 25) and reduces fever (26, 27, 28). Analogous to acetylsalicylic acid, the prototype of this class, this analgesic/antipyretic activity of ibuprofen occurs at lower doses than necessary for anti- inflammatory effects, which are thought to require sustained administration of higher individual doses (16).
Clinical studies indicate a duration of clinical effect for up to 8 hours for fever and up to 6 hours for pain.
Ibuprofen is rapidly absorbed after oral administration, with peak serum or plasma levels generally appearing within 1 to 2 hours. Oral absorption is estimated to be 80% of the dose. Both the rate of absorption and peak plasma concentrations are reduced when the drug is taken with food, but bioavailability as measured by total area under the concentration-time curve is minimally altered.
Ibuprofen, like most drugs of its class, is highly protein bound (>99% bound at 20 μg/mL) (29, 30). Tissue distribution of ibuprofen is also extensive in humans. Studies comparing synovial fluid levels with serum concentrations indicated that equilibration time post-ingestion occurred within approximately 3 to 5 hours (31).
It is rapidly metabolized through oxidation and glucuronic acid conjugation with urinary excretion of the inactive metabolites usually complete within 24 hours. Less than 10% is excreted unchanged in the urine (8).
Ibuprofen has an elimination half-life of approximately two hours.
Studies demonstrate no apparent clinically significant alterations in ibuprofen pharmacokinetics in the elderly (32).
Ibuprofen pharmacokinetics have also been studied in patients with alcoholic liver disease who have been assessed to have fair to poor hepatic function. Results suggest that, despite the liver being the primary organ of metabolism of ibuprofen, its kinetic parameters are not substantially altered by this condition (33).
While the mechanism of action of ibuprofen is not definitely known, the generally accepted mechanism is the inhibition of prostaglandin synthesis. Inhibition of prostaglandin biosynthesis prevents sensitization of tissues by prostaglandins to other inflammatory, pain and thermoregulatory mediators, hence accounting for the activity of ibuprofen and other nonsteroidal anti-inflammatory drugs against pain, inflammation and fever (16).
Inhibition of prostaglandin synthesis by ibuprofen has been demonstrated in several different experimental models: bull seminal vesicle microsomes (34), stomach, duodenum, kidney and brain of the rat, (35) microsomal preparations from rabbit brain and kidney medulla (36).
The analgesic efficacy of ibuprofen has been demonstrated in several animal models: phenylbenzoquinone-induced writhing in the mouse, acetylcholine-induced writhing in the mouse, the Randall-Selitto inflammed paw model in the rat, the mouse hot plate and adjuvant-induced arthritis model in the rat (37, 38, 39).
The antipyretic activity of ibuprofen has been demonstrated in yeast-induced fever in rats (37, 38, 39).
Several aspects of the pharmacokinetics of ibuprofen have been studied in vivo in rats, rabbits, dogs and baboons.
Studies in rats indicate that while limited absorption of ibuprofen occurs in the stomach, the principal site of absorption is the intestine. Single dose studies using C14 labelled ibuprofen in rats, rabbits and dogs show rapid absorption rates (40).
Tissue distribution studies performed in rats after both single and repeated doses of 20 mg/kg of C14 labelled ibuprofen demonstrate broad distribution with accumulation of radioactivity in the thyroid, adrenals, ovaries, fat and skin. Transplacental passage of ibuprofen was also noted with similar plasma levels measured in both the pregnant rats and fetuses (40).
Protein binding studies with plasma levels of 20 μg/mL indicate the percent bound in rats 96%, dogs 99%, baboons 95% and man 99% (29).
Four metabolites of ibuprofen have been found in the plasma of rabbits, three in rats, none in dogs, two in baboons and two in man, with the liver suggested as the principal organ of metabolism (40, 29). Excretion of metabolites was noted to varying degrees through both urine and feces indicating species variability in the bile and kidney excretion ratios.
Experimental data suggest that ibuprofen may inhibit the effect of low dose ASA (81-325 mg per day) on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400 mg was taken within 8 hours before or within 30 minutes after immediate-release ASA dosing, a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.
The pharmacokinetics of ibuprofen has also been studied in humans. Although there is little evidence of clinically significant age dependent kinetics in febrile children ages 3 months to 12 years (58), some differences in the pharmacokinetic parameters of volume of distribution and clearance have been observed between adults and children (59).
In-vivo studies indicate that ibuprofen is well absorbed orally with peak plasma levels usually occurring within 1 to 2 hours. A single 200 mg oral dose study in 6 fasting healthy men produced a peak plasma concentration of 15.0 μg/mL at 0.75 hr (12). Another study using a single oral 400 mg dose in humans produced a peak serum level of 31.9 + 8.8 μg/mL 0.5 hour after ingestion, and at 16 hours serum concentrations had dropped to 1 μg/mL (13). Comparable serum levels and time to peak within 1-2 hours were confirmed by other investigations with 200 mg and 400 mg solid doses (60, 31). A multiple dose study of administration of a 200 mg ibuprofen tablet three times a day for 2 weeks showed no evidence of accumulation of ibuprofen (29). As is true with most tablet and suspension formulations, Children’s MOTRIN suspension is absorbed somewhat faster than a tablet with a time to peak generally within one hour.
Ibuprofen, like most drugs of its class, is highly protein bound (>99% bound at 20 μg/mL) (29, 30). Based on oral dosing data there is an age-or fever-related change in volume of distribution for ibuprofen. Febrile children <11 years old have a volume of approximately 0.2 L/kg while adults have a volume of approximately 0.12 L/kg. The clinical significance of these findings is unknown (59). Tissue distribution of ibuprofen is also extensive in humans. Studies comparing synovial fluid levels with serum concentrations indicated that equilibration time post-ingestion occurred within approximately 3 to 5 hours (31).
Ibuprofen is extensively metabolized in humans with approximately 84% recoverable in the urine, primarily as conjugated hydroxy- and carboxy-metabolites, with only approximately l% excreted unchanged (8). The two major metabolites of ibuprofen in humans have been found to have no activity in the ultraviolet erythema test in guinea pigs and in the acetylcholine-induced mouse writhing test at doses of l0 mg/kg and l5 mg/kg respectively (38).
Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually complete 24 hours after the last dose. It has a biphasic plasma elimination time curve with a half-life of approximately 2.0 hours. There is no difference in the observed terminal elimination rate or half-life between children and adults, however, there is an age-or fever-related change in total clearance (59). This suggests that the observed difference in clearance is due to differences in the volume of distribution of ibuprofen, as described above. The clinical relevance of these differences in clearance is unknown, although extensive clinical experience with ibuprofen in children at the pertinent dosage range (5-10 mg/kg) indicates a wide margin of safety.
Not applicable.
Toxicity studies have been conducted using a variety of species, including: mice, rats, rabbits, guinea pigs and beagle dogs.
Single-dose acute toxicity studies indicate that ibuprofen in lethal doses depresses the central nervous system of rodents and that large doses are ulcerogenic in both rodents and nonrodents.
Ulcerogenesis may occur with both parenteral and oral administration indicating that the mechanism may have both a systemic as well as topical component.
Acute toxicity of ibuprofen in the rodent was studied in a number of models.
Single graded doses of ibuprofen were administered by oral intubation or by intraperitoneal or subcutaneous injection to groups of l0 male albino mice and male albino rats. Gross reactions were observed and mortalities recorded over a period of l4 days. The LD50 values determined by this method were 800 mg/kg orally and 320 mg/kg intraperitoneally in the mouse and l600 mg/kg orally and l300 mg/kg subcutaneously in the rat. Acute signs of poisoning were prostration in mice, and sedation, prostration, loss of righting reflex and labored respiration in rats. Death occurred within 3 days from perforated gastric ulcers in mice and intestinal ulceration in rats, irrespective of the route of administration (40).
Similar LD50 determinations in other strains of rats and mice are summarized in the following Table 1.
Table 1. Acute Toxicity in Rodents (LD50):
| Species | Route | LD50 Range (mg/kg) |
|---|---|---|
| Albino Mice(40,37) | Oral Intraperitoneal | 800-1000 320 |
| Albino Rats(40) | Oral Subcutaneous | 1600 1300 |
| Sprague Dawley Rat(61) | 1050 | |
| Long Evans Rat(62) | 1000 |
In a comparison of several non-steroidal anti-inflammatory drugs (NSAID) including ibuprofen, male rats were sacrificed and the stomachs removed and examined for ulceration either 3 or 24 hours after oral administration of various single doses of ibuprofen (63). Using a standard scoring technique a mean score for each dosage group was calculated and the ulcerogenic potential was expressed as a minimum ulcerogenic dose. The minimum oral ulcerogenic dose for ibuprofen in rats was calculated to be 6-13 mg/kg.
Another group studied the production of gastrointestinal lesions in the rat comparing ulcerogenic doses of ibuprofen and other NSAIDs after oral or intravenous administration (62). Both male and female Long Evans rats were used in all experiments. Prior to drug administration the animals were fasted for 8 hours. After treatment they were fed a normal diet and sacrificed after l7 hours. Gastric and intestinal mucosa was examined for presence of ulcers. The ulcerogenic dose in 50% of treated animals (UD50) was calculated. The UD50 following oral administration of ibuprofen was determined to be 70 mg/kg while for intravenous ibuprofen it was 210 mg/kg. The intestinal UD50 was 88 mg/kg following oral and 172 mg/kg with intravenous administrations. A calculated “severity index” of gastric lesions was higher by the oral than the IV route at all doses tested.
Studies of the ulcerogenic potential of ibuprofen are summarized in the following Table 2.
Table 2. Single Dose Ulcerogenicity Studies in Rodents:
| Species | Route | UD50*(mg/kg) | MUD** (mg/kg) |
|---|---|---|---|
| Long Evans Rat(62) | Oral IV | 70 210 | 50 - |
| Sprague Dawley Rat(63) | Oral | - | - |
Acute toxicity has also been studied in dogs.
Various single oral doses of ibuprofen were administered to dogs with subsequent hematologic examination and biochemical analyses of blood and urine, and examination of feces for occult blood (40). Gross examination of the major organs occurred after the animals were sacrificed. No ill effects were seen following doses of 20 or 50 mg/kg. Oral doses of 125 mg/kg or greater produced emesis, scouring, albuminuria, fecal blood loss and erosions in the gastric antrum and pylorus.
Multiple dose ulcerogenicity studies of ibuprofen have also been conducted.
Rats were dosed by the oral route for a specific number of consecutive days, then sacrificed for examination. The ulcerogenic effect of oral ibuprofen was graded and reported by various scoring systems such as percent of animals in which ulcers were produced by a specific dose, or the UD50.
In one typical such study, Long Evans rats were administered comparative NSAIDs orally once a day for 5 days (62). The gastric and small intestinal mucosa were then examined for ulceration. The UD50, MUD and potency ratio of the drugs tested were calculated. The minimal ulcerogenic doses of ibuprofen were 25 mg/kg for the stomach and 50 mg/kg for the intestine.
Similar studies of multiple dose ulcerogenic potential of ibuprofen are summarized in the following Table 3.
Table 3. Multiple Oral Dose Toxicity Studies:
| Species | Daily Dose | Duration | Ulcerogenic Factor |
|---|---|---|---|
| Albino Rat(64) | 400 mg/kg | 30 hours | Ulcers in 100% |
| Albino Rat(37) | 4 days | UD50 = 455 mg/kg/day UD28 = 240 mg/kg/day | |
| Long Evans Rat(62) | 5 days | MUD = 25-50 mg/kg/day | |
| Sprague Dawley Rat(65) | 5.8-225 mg/kg | 10 days | None |
| Albino Rat(40) | 7.5 mg/kg 180 mg/kg | 26 weeks 26 weeks | None Ulcers in 20% |
| Dog(40) | 4 mg/kg 8 mg/kg 16 mg/kg | 30 days 30 days 30 days | None 100% 100% |
No other organ systems were generally noted to be significantly affected by these chronic administration studies. In one 30-day study (66), Wistar rats receiving 157 mg/kg/day ibuprofen had serum transaminase levels approximately double of those of a control, untreated group. Lower doses of ibuprofen in the same study had no significant effect on the activity of these enzymes.
Chronic toxicity studies in dogs demonstrated no gross or clinical signs of toxicity at 4, 8 or 16 mg/kg/day for 30 days (40). However, in all dogs given 8 or 16 mg/kg/day, postmortem examination revealed gastric ulcers or erosions. No lesions were observed in dogs given 4 mg/kg/day.
A more complete assessment of chronic toxicity of ibuprofen in dogs studied the effects of administration of oral doses of 0, 2, 4 or 26 mg/kg/day over 26 weeks (40). Periodic blood, urine and fecal sample analyses were performed. Histologic examination of selected organs and tissues was performed at the completion of the study. During the 26 week period, some reversible signs of gastrointestinal disturbance characterized by frequent vomiting, diarrhea, occasional passage of fresh blood and weight loss occurred in the 2 female dogs but not the males receiving 16 mg/kg ibuprofen. Occult blood was irregularly detected in fecal samples but urinalysis, liver function tests and other hematologic and blood biochemical values were not altered significantly. Gross examination of organs was normal except for ulcerative lesions in the gastrointestinal tract of organs of all dogs receiving 16 mg/kg/day. Dogs given 2 and 4 mg/kg/day suffered no adverse reactions or gastrointestinal damage.
A study to evaluate the potential carcinogenic activity of ibuprofen involved administration of a minimum of 100 mg/kg/day to mice for 80 weeks and 60 mg/kg/day to rats for 2 years (67). The proportion of animals with tumors of all types examined did not differ from those in the control group. The studies confirm that in the rat and mouse, ibuprofen does not induce tumors of the liver or other organs. Further, despite prolonged treatment, no other drug-induced hepatic lesions were seen in either species.
Teratogenicity studies of ibuprofen have been conducted in rabbits and rats (40). Results of the experiments indicate that ibuprofen is not teratogenic when given in toxic doses to rabbits nor is there embryotoxic or teratogenic activity in pregnant rats even when administered in ulcerogenic doses.
Effects of ibuprofen on circular strips of fetal lamb ductus arterious indicate that exposure may produced contraction of the ductus (68). Such an effect might be anticipated because of the known prostaglandin inhibiting properties of ibuprofen.
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