Pharmacodynamics<unk>  appears to exert its effects through two mechanisms: the inhibition of cyclooxygenase and actions of its metabolite AM404. Supporting the first mechanism, pharmacologically and in its side effects,<unk>  is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting COX-1 and COX-2 enzymes and especially similar to selective COX-2 inhibitors.<unk>  inhibits prostaglandin synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of arachidonic acid and peroxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of<unk> . Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of<unk> . Accordingly, the anti-inflammatory action of<unk>  is slight. The anti-inflammatory action of<unk>  (via COX inhibition) has also been found to primarily target the central nervous system and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding. The second mechanism centers on the<unk>  metabolite AM404. This metabolite has been detected in the brains of animals and cerebrospinal fluid of humans taking<unk> . Apparently, it is formed in the brain from another<unk>  metabolite 4-aminophenol by action of fatty acid amide hydrolase. AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor. This and other research indicate that cannabinoid system and TRPV1 may play an important role in the analgesic effect of<unk> . Pharmacokinetics After being taken by mouth,<unk>  is rapidly absorbed from the small intestine, while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach emptying and absorption, but the total amount absorbed stays the same. In the same subjects, the peak plasma concentration of<unk>  was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate, but not high protein or high fat, food decreases<unk>  peak plasma concentration by four times. Even in the fasting state, the rate of absorption of<unk>  is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours.<unk> 's bioavailability is dose-dependent: it increases from 63% for 500mg dose to 89% for 1000mg dose. Its plasma terminal elimination half-life is 1.92.5 hours, and volume of distribution is roughly 50L. Protein binding is negligible, except under the conditions of overdose, when it may reach 1521%. The concentration in serum after a typical dose of<unk>  usually peaks below 30μg/mL (200μmol/L). After 4 hours, the concentration is usually less than 10μg/mL (66μmol/L). Important pathways of<unk>  metabolism.<unk>  is metabolized primarily in the liver, mainly by glucuronidation and sulfation, and the products are then eliminated in the urine (see the Scheme on the right). Only 25% of the drug are excreted unchanged in the urine. Glucuronidation by UGT1A1 and UGT1A6 accounts for 5070% of the drug metabolism. Additional 2535% of<unk>  is converted to sulfate by sulfation enzymes SULT1A1, SULT1A3, and SULT1E1. A minor metabolic pathway (5-15%) of oxidation by cytochrome P450 enzymes, mainly by CYP2E1, forms a toxic metabolite known as NAPQI (N-acetyl-p-benzoquinone imine). NAPQI is responsible for the liver toxicity of<unk> . At usual doses of<unk> , NAPQI is quickly detoxified by conjugation with glutathione. The non-toxic conjugate<unk> -GSH is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by the large amount of formed NAPQI, and NAPQI binds to mitochondria proteins of the liver cells causing oxidative stress and toxicity. Yet another minor but important direction of metabolism is deacetylation of 12% of<unk>  to form p-aminophenol. p-Aminophenol is then converted in the brain by fatty acid amide hydrolase into AM404, a compound that may be<unk> tially responsible for the analgesic action of<unk> .
Paracetamol
Ketoprofen
Ibuprofen
Ketorolac
Meloxicam
Lornoxicam
Etodolac
Loxoprofen