Pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans

@article{Vree1993PharmacokineticsON,
  title={Pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans},
  author={Tom B. Vree and M van den Biggelaar-Martea and C. P. W. Verwey-van Wissen and J B Vree and Pieter J.M. Guelen},
  journal={Biopharmaceutics \& Drug Disposition},
  year={1993},
  volume={14}
}
The aim of this investigation was to assess the pharmacokinetics of naproxen in 10 human subjects after an oral dose of 500 mg using a direct HPLC analysis of the acyl glucuronide conjugates of naproxen and its metabolite O‐desmethylnaproxen. The mean t1/2 of naproxen in 9 subjects was 24.7 ± 6.4 h (range 16 to 36 h). The t1/2 of 7.4 as found in subject number 10 must, therefore, be regarded as an extraordinary case (p <0.0153). Naproxen acyl glucuronide accounts for 50.8 ± 7.32 per cent of the… 
Disposition of naproxen, naproxen acyl glucuronide and its rearrangement isomers in the isolated perfused rat liver
TLDR
Comparisons suggest that isoNAG is a better substrate for adduct formation with liver proteins than NAG, and formation of covalent NAP-protein adducts in perfusate were greater in isoNAg-dosed perfusions.
Conjugation of desmethylnaproxen in the rat--a novel acyl glucuronide-sulfate diconjugate as a major biliary metabolite.
TLDR
No evidence for a diglucuronide metabolite of DMN was found in either bile or urine of the DMN-dosed rats, and tentative identification of the two unknown peaks as the phenolic glucuronide ofDMN and a novel acyl glucuronides-sulfate diconjugate of DMn was confirmed.
S-Naproxen and desmethylnaproxen glucuronidation by human liver microsomes and recombinant human UDP-glucuronosyltransferases (UGT): role of UGT2B7 in the elimination of naproxen.
TLDR
UGT2B7 is responsible for human hepatic naproxen acyl glucuronidation, which is the primary elimination pathway for this drug.
Clinical Pharmacokinetics of Naproxen
TLDR
Naproxen is a stereochemically pure nonsteroidal anti-inflammatory drug of the 2-arylpropionic acid class and relationships between the total and unbound plasma concentration, unbound synovial fluid concentration and therapeutic effect have been established.
Sulphation of o-desmethylnaproxen and related compounds by human cytosolic sulfotransferases.
TLDR
These studies indicate that O-DMN is sulphated by SULT1A1, B1 and 1E1, which may have a role in the first pass metabolism of O- DMN.
Probenecid inhibits the glucuronidation of indomethacin andO-desmethylindomethacin in humans
TLDR
This pilot experiment shows that probenecid reduced the acyl glucuronidation of indomethacin by 50% and completely inhibited the formation ofO-desmethylindometHacin acyl and ether glucuronide.
Pharmacokinetics and Protein Adduct Formation of the Pharmacologically Active Acyl Glucuronide Metabolite of Mycophenolic Acid in Pediatric Renal Transplant Recipients
The acyl glucuronide metabolite (AcMPAG) of mycophenolic acid (MPA) has been found to possess both immunosuppressive and pro-inflammatory activity in vitro. In this study its pharmacokinetics were
Stereoselective binding properties of naproxen glucuronide diastereomers to proteins
TLDR
The stability of naproxen glucuronide (NAP-G) diastereomers was investigated in buffer, 0.3% and 3% human serum albumin (HSA) solutions, and human plasma, and in vitro irreversible binding of NAP-Gs to HSA, human and rat plasma proteins was also investigated.
Acyl Glucuronide Drug Metabolites: Toxicological and Analytical Implications
TLDR
This review summarizes the most recent evidence concerning biologic and toxicologic effects of acyl glucuronide metabolites of various drugs and discusses their relevance for drug monitoring.
Acyl glucuronides: the good, the bad and the ugly.
TLDR
A review of the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives concluded that these might be attenuated substantially in vivo by rapid clearance of the conjugates.
...
...

References

SHOWING 1-10 OF 16 REFERENCES
Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine.
TLDR
There was no difference between PM and EM in the AUC of C6G and NCG, nor in the partial clearances by N-demethylation and glucuronidation, Norcodeine, norcodeine (NC), NC-glucuronide (NCG), morphine, and normorphine (NM) were investigated after a single oral dose of 50 mg codeine phosphate.
Negligible excretion of unchanged ketoprofen, naproxen, and probenecid in urine.
TLDR
It is possible that no unchanged ketoprofen, naproxen, or probenecid is excreted in urine, and attention should be given to potential conjugate hydrolysis whenever the pharmacokinetics of carboxylic acids are studied.
Studies on the fate of naproxen. II. Metabolic fate in various animals and man.
TLDR
The animals whose urinary metabolic profiles were the nearest to that of man were the guinea pig and mouse, while the animals that differed most from man in this regard were the rat and miniature pig.
Interindividual and interethnic differences in the demethylation and glucuronidation of codeine.
TLDR
The 8 h urinary excretion of codeine and seven of its metabolites was compared in 149 healthy Swedish Caucasians and 133 healthy Chinese following a single oral dose of 25 mg codeine phosphate and there was a 160-fold interindividual variation in this MR.
Pharmacokinetics and metabolism of codeine in humans
TLDR
Two out of eight volunteers were unable to O‐dealkylate codeine into morphine and lack therefore the cytochrome P450 IID6 isoenzyme, which is 10 times higher than that of codeine.
Relationship of serum naproxen concentration to efficacy in rheumatoid arthritis
TLDR
Twenty‐four patients with rheumatoid arthritis were tested in a randomized, double‐blind, Latin‐square comparison of 250, 750 and 1500 mg of naproxen daily, finding no order effect or change in baseline was found.
...
...