Naproxen metabolism

A second type of nonhyperbolic saturation kinetics became apparent during studies on the metabolism of naproxen to desmethylnaproxen (32). Studies with human liver microsomes showed that naproxen metabolism has biphasic kinetics and is activated by dapsone (T. Tracy, unpublished results). The unactivated data shows what appears to be a typical concentration profile for metabolism by at least two different enzymes. However, a similar biphasic profile was obtained with expressed enzyme (25). This biphasic kinetic profile is observed with the two-substrate model when V/rn2 > Eml and Kml Km2. The appropriate equation for the two-site model when [S] < Kml is... 

Another example of reactions that can be described by Figure 7 is the effect of dapsone on naproxen metabolism by CYP2C9. In this case, dapsone makes the biphasic naproxen curve more hyperbolic. Finally, one can expect similar influences on reactions that show substrate inhibition. If ESB has a metabolic rate similar to ES, one would expect activation at high substrate concentrations. Conversely, if the rate is similar to ESS, inhibition would be expected at intermediate substrate concentrations, with little effect at Vm. 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Common NSAIDs include aspirin, ibuprofen, indomethacin, naproxen, and ketoprofen. Even though anti-inflammatories generally target cyclooxygenase, there are apparent differences in the details of how they relieve pain. For example, aspirin acts by primarily inhibiting the COX-dependent synthesis of eicosanoids, which are end products of metabolism of essential fatty acids including prostaglandin... 

UGT 2 UGT2B7 IPD Reduced metabolism in 10-15% (W) population Ibuprofen, Naproxen, Irinotecan... 

Some NSAIDs (e.g, diclofenac, ibuprofen, naproxen, piroxicam) are actively metabolized by CYP2C9, which may be a site of possible interaction with inhibitors and inducers of this isoenzyme. 

NS AIDs ANTIGOUT DRUGS-PROBENECID T levels of indometacin, ketorolac and possibly dexketoprolien, ketoprofen, naproxen, tenoxicam and tiaprofenic acid Probenecid competitively inhibits renal metabolism of these NSAIDs Watch for signs of toxicity of these NSAIDs. Consider using an alternative NSAID. The manufacturers of ketorolac advise avoiding co-adminis-tration of ketorolac and probenecid... 

NAPROXEN MODAFINIL May cause 1 naproxen levels if CYP1A2 is the predominant metabolic pathway and alternative metabolic pathways are either genetically deficient or affected Modafinil is moderate inducer of CYP1A2 in a concentration-dependent manner Be aware... 

Nothing more serious than nausea and indigestion have been reported after 25 g of naproxen (30), whereas 35 g caused an epileptic fit (31). Metabolic acidosis, loss of consciousness, seizures, and apnea have been reported after the ingestion of more than 10 g (32). 

Naproxen inhibits the metabolism and renal excretion of probenecid, prolonging its half-life (34). 

Martinez R, Smith DW, Frankel LR. Severe metabolic acidosis after acute naproxen sodium ingestion. Ann Emerg Med 1989 18(10) 1102-4. 

Pseudoporphyria is a photodistributed bullous disorder with clinical and histological features similar to those of porphyria cutanea tarda, but without accompanying abnormalities of porphyrin metabolism. Drugs, in particular NSAIDs and sulfur-containing diuretics, often cause pseudoporphyria (193). Pseudoporphyria associated with naproxen (15 mg/kg/day) has been reported in a child (194). 

Various arylpropionic acids show similar specificity. For most, if not all, the (5) enantiomer is the pharmacologically active one, whereas the R) enantiomer is usually much less active, although the ratio of iS)/ R) activity varies from drug to drug (and species to species). Only one of these drugs, however, is administered as the separated (S) enantiomer (naproxen, Naprosyn ). Normally these drugs are considered safe, and one cannot readily differentiate between the relative activities of the (S) and (R) forms because the in vivo half-life is very short, typically one or two hours. In patients with impaired renal function, where clearance is much slower, however, problems can arise. From in vivo studies of ibuprofen, it was established that the (S)-(-l-) isomer was responsible for antiinflammatory activity. In vivo, however, the (/ )-(-) isomer may become active because there is stereoselective inversion from R) to (S) (but not from 5 to R) in vivo with a half-life of about two hours. This inversion apparently proceeds by stereoselective formation of the coenzyme A (CoA) ester of the (f )-(-)-arylpropionic acid, followed by epimerization and release of the (S)-(+)-enantiomer. This epimerization is observed in vivo before the oxidative metabolism. Such inversion from (R) to (S) in vivo is also known for fenoprofen and benoxa-profen, and is expected to occur for most of the drugs of this series. ... 

Example Ibuprofen (Motrin, Advil, Nuprin) naproxen (Naprosyn) (Aleve is a similar OTC drug) Oxaprozin (Daypro) ketoprofen (Orudis). Route PO Pregnancy category B Pharmacokinetic Absorbed from the GI tract, metabolized in the liver and primarily excreted in urine ... 

Examples of therapeutic compounds metabolized by CYP2C9 include nonsteroidal antiinflammatory (NSAID) medications, irbesartan, naproxen, and fluvastatin (see Table 43-3). Proposed dose adjustments based on phenotype have been published for CYP2C9 drug substrates such as warfarin, glipizide, tolbutamide, and phenytoin. ... 

In vivo studies. - Many natural compounds and therapeutic drugs form glycosides during transport through the gastrointestinal tract. Mortenson et al have used directly coupled LC- H NMR to various acylated isomers of the glucuronide of S-naproxen in human urine samples. This technique has also been used to study the metabolic variation in rats to identify metabolic populations in urine. 

Describe the metabolism and elimination of naproxen and naproxen sodium. 

Other important metabolites of O-glucuronidation are acylglucuronides. They are formed by esterification of carboxylic acids with glucuronic acid. Many therapeutic agents such as arylacetic acids (diclofenac, diflunisal), aliphatic acids (valproic acid) and arylpropionic acids (ketoprofen, naproxen) are metabolized as acylglucuronides (Fig. 31.37). 

Warfarin reduces the synthesis of prothrombin and several other clotting factors. Carbamazepine and rifampin interfere with this action by increasing the metabolism of warfarin. Cholestyramine decreases the oral absorption of warfarin and other acidic drugs. Vitamin K is the antidote to excessive effects of warfarin. Antiplatelet drugs such as naproxen enhance the anticoagulant effects of warfarin. The answer is (C). 

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